Grandmaternal smoking during pregnancy and grandchild health: A systematic review and meta-analysis

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However, emerging evidence suggests that the adverse effects of smoking during pregnancy may be transmitted across generations. We conducted a systematic review to comprehensively summarize evidence on the association between grandmaternal smoking during pregnancy and health outcomes in the grandchild. Methods We searched MEDLINE, EMBASE, and 10 other databases from inception to March 02, 2021, updated on October 18, 2021, to identify analytic epidemiologic studies (prospective or retrospective cohort and case-control design) investigating the association between grandmaternal smoking during pregnancy and multiple health outcomes in the grandchild in all countries and settings. Three investigators independently screened records, extracted data, and assessed study quality using the Effective Public Health Practice Project (EPHPP) tool. Random-effects robust variance estimation was used to combine effect estimates whenever possible, separately for maternal and paternal line. Results Twenty-four reports from 15 unique studies with 23 health outcomes and 231,478 grandchildren were included. The overall study quality was moderate. In maternal line, grandmaternal smoking during pregnancy was associated with an increased risk of asthma (seven studies, 148,527 grandchildren, risk ratio (RR) 1.10, 95% CI 1.02 to 1.18) and higher birth weight (four studies, 19,478 grandchildren, mean difference (g) 40.04, 95% CI 22.60 to 57.49) in the grandchild. There was suggestive evidence that maternal grandmaternal smoking was associated with increased risks of acute lymphoblastic leukaemia, any cancer, autism, and attention deficit hyperactivity disorder, decreased risks of early-onset myopia and small birth weight for gestational age, and higher birth length and body mass index at birth. In paternal line, grandmaternal smoking during pregnancy was not associated with asthma (four studies, 41,069 grandchildren, RR 1.01, 95% CI 0.85 to 1.19), but there was suggestive evidence for lower intelligence quotient scores and decreased risks of early-onset myopia and intolerance to loud sound. Conclusions The effects of maternal smoking during pregnancy may not be limited to the exposed child, but be transmitted to the grandchild, possibly through germline epigenetic inheritance. Further public health efforts are warranted to strengthen smoking cessation programs for pregnant women. acute lymphoblastic leukaemia asthma attention deficit hyperactivity disorder autism cancer grandchild grandmother intelligence quotient smoking during pregnancy systematic review Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Globally, the prevalence of maternal smoking during pregnancy is estimated to be around 2% [ 1 ]. However, in many countries, smoking during pregnancy is still common. More than 10% of pregnant women smoked during pregnancy in 29 (17%) of 174 countries and more than 20% in 12 (7%) countries [ 1 ]. Specifically, the prevalence of smoking during pregnancy was on average 8% in Europe (ranging from 0.5–38%) and 17% in the USA [ 1 ]. Notably, more than 70% of pregnant women who smoked during pregnancy smoked daily rather than occasionally [ 1 ]. With decades of research, smoking during pregnancy has been linked to a host of detrimental effects on the exposed child. For example, smoking during pregnancy is associated perinatally with low birth weight [ 2 ], preterm birth [ 3 , 4 ], various birth defects [ 5 ], still birth [ 6 ], and neonatal death [ 7 ]; and postnatally with sudden infant death syndrome [ 8 ], asthma [ 9 ], obesity [ 10 ], high blood pressure [ 11 ], low intelligence quotient (IQ) scores [ 12 ], conduct problems [ 13 ], and attention deficit hyperactivity disorder (ADHD) [ 14 ]. These findings suggest that smoking during pregnancy may affect offspring’s health already in utero , with potentially life-long negative health consequences. The biologic mechanisms by which maternal smoking may lead to diverse adverse health in the offspring are complex. Extensive human and laboratory studies have shown that cigarette smoke contains more than 7,000 chemicals, many of which (e.g., nicotine, carbon monoxide) can cross the placental barrier to influence fetal programming or have a direct toxicologic effect on the fetus [ 15 , 16 ]. In recent years, it is increasingly recognized that many of the mechanisms are mediated epigenetically [ 17 , 18 ]. The epigenome refers to the biochemical information that lies ‘over and above’ the DNA sequence and regulates the expression of genes through mechanisms such as DNA methylation (DNAm), histone modifications and non-coding RNAs [ 19 , 20 ]. There is a growing body of literature that smoking during pregnancy is associated with numerous epigenetic alterations in the exposed child, which may in turn affect health outcomes [ 17 , 18 ]. For example, many studies consistently found that DNAm at specific gene loci mediated in part the relationship between maternal smoking and offspring low birth weight [ 21 – 26 ]. An increasing number of human epigenome-wide association studies showed that DNAm marks at some specific gene regions were associated with ADHD and asthma, suggesting that epigenetic mechanisms may play an important role in their etiology [ 27 – 39 ]. In rat models, maternal nicotine exposure during pregnancy (F0) induced epigenetic changes not only in the first generation (F1), but also in the germ cells of F1 generation that form the second generation (F2) (termed as intergenerational epigenetic inheritance) and of F2 generation that form the third generation (F3) (as transgenerational epigenetic inheritance) [ 40 – 42 ]. Furthermore, recent human epigenome-wide association studies found that grandmaternal smoking during pregnancy was associated with differential DNAm in the grandchild [ 43 , 44 ]. While the detrimental health effects of smoking during pregnancy on the exposed child are well established, it is unclear whether these effects are transmitted to the subsequent generation(s) through epigenetic inheritance. Whilst the plausibility of epigenetic inheritance is being elucidated [ 20 , 45 , 46 ], a number of epidemiologic intergenerational studies have investigated the impact of grandmaternal smoking during pregnancy on various health outcomes in the grandchild, but results are inconsistent for some outcomes (e.g., birth weight, asthma) [ 47 – 50 ]. To elucidate the underlying evidence, we undertook a systematic review of observational epidemiologic studies investigating the association between grandmaternal smoking during pregnancy and multiple health outcomes in the grandchild. We sought to comprehensively summarize the available evidence on the potential intergenerational transmission of the effects of maternal smoking during pregnancy. Methods The protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42017084039). This study was reported as per the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline [ 51 ] (Additional file 1). Ethical approval was not required for this study. Literature search and eligibility criteria We searched MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, CINAHL, Google Scholar, Scopus, Global Health, PsycINFO, Zetoc, CAB International and WHO Global Health Library from inception to March 02, 2021. The database search was updated on October 18, 2021. No language restriction was applied. The search strategies are available in the PROSPERO protocol. Three investigators (GQZ, YL and HHZ) independently screened the titles and/or abstracts and reviewed full-text articles for eligibility. Any discrepancies were resolved by discussion or by a third investigator (BIN). We also manually checked the references of included studies and relevant reviews to identify additional eligible studies. Studies were selected for inclusion if they met the following Population, Exposure, Comparator, Outcome, Study design (PECOS) criteria: 1) Population: grandmother-mother/father-child triads of any ethnicity in any country or setting; 2) Exposure: maternal grandmaternal smoking during pregnancy (i.e., grandmother smoked any amount of cigarettes when pregnant with the mother) or paternal grandmaternal smoking during pregnancy (i.e., grandmother smoked any amount of cigarettes when pregnant with the father); 3) Comparator: no maternal or paternal grandmaternal smoking during pregnancy; 4) Outcome: any health outcome in the grandchild of any age; 5) Study design: analytic epidemiologic studies (prospective or retrospective cohort and case-control design). We also included studies investigating the effects of both grandmaternal and maternal smoking during pregnancy relative to neither of them smoked during pregnancy. We excluded reviews, commentaries, studies of grandmaternal smoking not during pregnancy, and studies of indirect outcome measures (e.g., DNAm, dietary inflammatory index, lung function parameters). For conference abstracts, corresponding authors were contacted to request additional data. If no information was provided, they were excluded from our review (eTable 1 in Additional file 2). Data extraction and quality assessment Three investigators (GQZ, YL and HHZ) independently extracted data by outcome using a customized data extraction form. For each article, we extracted first author, year of publication, country, study design, exposure group, reference group, sex and age of the grandchild, outcome examined, number of cases and controls in case-control studies or total population in cohort studies for binary outcomes, number of total population in cohort studies for continuous outcomes, type of effect measure (mean difference (MD), risk ratio (RR), odds ratio or hazard ratio), and maximally-adjusted effect estimate with 95% confidence interval (CI). When studies reported multiple effect estimates for different exposure levels relative to non-smoking [ 47 , 49 , 52 , 53 ], or estimates relative to a reference group other than non-smoking [ 54 ], corresponding authors were contacted to obtain the estimates comparing smoking versus non-smoking. We received the requested data from three studies [ 47 , 49 , 54 ]. We categorized outcomes according to the International Classification of Diseases 11th Revision (ICD-11) [ 55 ]. Three investigators (GQZ, YL and HHZ) independently assessed the risk of bias of included studies by outcome using the Effective Public Health Practice Project (EPHPP) tool [ 56 ]. The EPHPP tool consists of six domains: study design, selection bias, confounders, exposure measurement, outcome measurement and statistical analysis. Each domain is rated as strong, moderate, or weak. Disagreements during data extraction and quality assessment were resolved by discussion or by a third investigator (BIN). Data synthesis and analysis We developed a priori an analysis protocol for this review (Additional file 3), which was adapted from our earlier work [ 57 ]. We used the random-effects robust variance estimation (RVE) method to calculate the summary average effect and its 95% CI [ 58 ]. The RVE method does not require any distributional assumptions on the population effects, can accommodate dependence among effect estimates (e.g., multiple estimates based on the same individuals at different time points, or computed using a common control group), and can provide correct inference even in meta-analyses with a small number of studies [ 58 , 59 ]. We quantified the extent of heterogeneity by estimating the standard deviation of population effects [ 60 , 61 ]. To evaluate the robustness of meta-analysis results to potential publication bias, we calculated the S-value [ 62 ], which represents the severity of publication bias that would hypothetically be required to shift the summary estimate to the null. For binary outcomes, we also calculated the E-value [ 63 – 65 ], which assesses how strong residual confounding would have to be to “explain away” an observed exposure-outcome association. The primary analyses focused on the average effects of grandmaternal smoking during pregnancy. These analyses were conducted separately for maternal and paternal line. Subgroup analyses were conducted according to maternal smoking status during pregnancy (smoking versus non-smoking) and sex of the grandchild (boys versus girls). We also conducted analyses for the effects of grandmaternal and maternal smoking during pregnancy in combination compared to neither of them smoked during pregnancy. For binary outcomes, all estimates were converted to the RR scale [ 63 , 66 ], and results were presented on that scale. All statistical analyses were performed using R software (version 4.0.4) [ 67 ]. The R scripts and datasets are respectively available in Additional file 4 and at the Open Science Framework. Results Characteristics of included studies Overall, we identified 1,152 records, scrutinized 49 full-text articles, and ultimately included 24 reports from 15 unique studies, including 18 reports from nine prospective cohort studies [ 48 – 50 , 53 , 54 , 68 – 80 ], three reports from three retrospective cohort studies [ 47 , 52 , 81 ], one report from one nested case-control study [ 82 ], and two reports from two case-control studies [ 83 , 84 ]. These reports were published between 2003 and 2021. Figure 1 shows the study selection process. Studies excluded at the full-text screening stage with reasons for their exclusion are available in eTable 1 in Additional file 2. Characteristics of the included studies are summarized in Table 1 . Figure 2 presents a summary of quality assessment by outcome across all included studies. Each EPHPP domain judgment for each outcome is available in eTable 2 in Additional file 2. Table 1. Characteristics of observational epidemiologic s tudies i nvestigating grandmaternal s moking during p regnancy and h ealth o utcomes in the g randchild Study Country Study design Participants Exposure assessment Outcome assessment Confounding factors adjusted Sampling method, source No. recruited/ analyzed Diseases of the respiratory system Accordini 2018 [74] Europe a , Australia Prospective cohort Sampling method: all children Children born from parents who participated in the ECRHS I and III Maternal line: 5,002/4,666 Paternal line: 4,563/4,192 Parent report at ECRHS I Parent-reported ever asthma with or without nasal allergies in children aged 0–51 years Grandmother’s and grandfather’s ever asthma and education level, maternal and paternal ever asthma, age, smoking and education level, and offspring’s gender and age Bråbäck 2018 [47] Sweden Retrospective cohort Sampling method: general population Children born after June 31, 2005, from all mothers born between 1982-1986 in Sweden Maternal line: 15,265/10,329 Paternal line: 15,265/10,329 Grandmother report at gestational week 8-12 Purchase of any asthma medication (inhaled steroid and/or leukotriene antagonist) by age 6 years Maternal smoking habits, maternal and paternal grandmother’s age, level of education, social welfare, BMI and asthma medication, maternal and paternal grandfather’s asthma medication, maternal and paternal age, sex of the child, and county of residence at mother’s and father’s birth Li 2005 [82] USA Nested case-control Sampling method: controls were countermatched on in utero exposure to maternal smoking within grade, sex, and community of residence Cases: asthmatic children from public schools (grades 4, 7, 10) in 12 southern California communities in 1993; Controls: non-asthmatic children from the same cohort Maternal line: Cases: 338/235 Controls: 570/335 Mother report Parent-reported doctor-diagnosed asthma in the first 5 years of life Grade, sex, community of residence, race/ethnicity, gestational age, and secondhand smoke exposure Table 1. Characteristics of observational epidemiologic s tudies i nvestigating grandmaternal s moking during p regnancy and h ealth o utcomes in the g randchild (continued) Study Country Study design Participants Exposure assessment Outcome assessment Confounding factors adjusted Sampling method, source No. recruited/ analyzed Lodge 2018 [52] Sweden Retrospective cohort Sampling method: general population Children born between 1996-2010, from all mothers born between 1982-1986 in Sweden Maternal line: 81,550/48,971 Grandmother report at gestational week 10-12 Purchase of any asthma medication (beta agonist, inhaled steroid, or leukotriene antagonist) by age 6 years Child’s gender and birth order, maternal nicotine exposure (smoking and snus), mother’s years of education, family allowance, birth order, residence at childbirth, and age, grandmother’s residence at childbirth, years of education, social allowance, asthma, age and BMI, and proxy for grandfather’s smoking Magnus 2015 [77] Norway Prospective cohort Sampling method: general population Children born from all pregnant women in 1999-2008 in Norway Maternal line: 110,291/46,564 Mother report at 18 gestational weeks Current asthma at age 3 and 7 years based on mother-reported asthma diagnosis/symptoms and/or dispensed asthma medications Maternal age, parity, education, salary, pre-pregnancy BMI, asthma and smoking during pregnancy Mahon 2021 [78] The Netherlands Prospective cohort Sampling method: all children Children whose parents participated in the LifeLines Cohort Study Maternal line: 167,548/30,546 Paternal line: 167,548/20,923 Parent report Grandchild- or parent-reported asthma from 4 to 50 years of age Gender, maternal smoking, current or former smoking, passive environmental smoke exposure in childhood, maternal age, birth weight, gestational age, breast feeding and socioeconomic status Miller 2014 [48] UK Prospective cohort Sampling method: general population Children born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992 Maternal line: NR/6,881 Paternal line: NR/5,625 Parent report during pregnancy Mother-reported doctor-diagnosed asthma ever at age 7 to 8 years in association with a history of wheezing in the preceding 12 months Family history of asthma, gestation, parity, maternal education, breastfeeding, the amount the mother smoked during pregnancy, paternal smoking in pregnancy and exposure of the child to environmental tobacco smoke Table 1. Characteristics of observational epidemiologic s tudies i nvestigating grandmaternal s moking during p regnancy and h ealth o utcomes in the g randchild (continued) Study Country Study design Participants Exposure assessment Outcome assessment Confounding factors adjusted Sampling method, source No. recruited/ analyzed Disorders of newborn related to length of gestation or fetal growth Ding 2017 [49] USA Prospective cohort Sampling method: all children Children born from women who participated in Nurses’ Health Study II (the Growing Up Today Study 2) Maternal line: 10,907/5,759 Grandmother report Mother-reported birth weight Grandmother’s gestational age, age at birth, level of education, consumption of alcohol, vegetable, fruit and meat, physical activity and weight gain during pregnancy, and mothers’ pre-pregnancy BMI, smoking during pregnancy, social-economic status, and diet score and physical activity during pregnancy Gustavson 2017 [75] Norway Prospective cohort Sampling method: general population Children born from all pregnant women in 1999-2008 in Norway Maternal line: NR/82,550 Mother report at 18 gestational weeks Birth weight records from the Medical Birth Registry of Norway Maternal and paternal age, education, and ADHD symptoms, maternal (pre-pregnancy) and paternal BMI, maternal smoking and alcohol consumption during pregnancy and parity, child’s birth year, and geographical region Hyppönen 2003 [76] UK Prospective cohort Sampling method: general population Children born from all mothers who were born from 3 to 9 March 1958 in England, Scotland, and Wales Maternal line: NR/9,028 Grandmother report Mother-reported birth weight Child’s gestational age, sex and birth order, and maternal smoking, height, BMI, and birth weight Table 1. Characteristics of observational epidemiologic s tudies i nvestigating grandmaternal s moking during p regnancy and h ealth o utcomes in the g randchild (continued) Study Country Study design Participants Exposure assessment Outcome assessment Confounding factors adjusted Sampling method, source No. recruited/ analyzed Miller 2014 [72] UK Prospective cohort Sampling method: general population Children born from all pregnant women who did not smoke during pregnancy in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992 Maternal line: NR/8,188 Paternal line: NR/6,773 Parent report during pregnancy Birth weight, birth length, head circumference and BMI, measured by study staff Child’s gestational age, maternal age, parity, education, birth weight, alcohol use and housing tenure, and paternal smoking at the start of pregnancy Pembrey 2014 [50] UK Prospective cohort Sampling method: general population Children born from all pregnant women who smoked during pregnancy in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992 Maternal line: NR/3,502 Paternal line: NR/2,354 Parent report during pregnancy Birth weight, birth length, head circumference and BMI, measured by study staff Child’s gestational age, maternal age, parity, education, birth weight, alcohol use and housing tenure, and paternal smoking at the start of pregnancy Rillamas-Sun 2014 [79] USA Prospective cohort Sampling method: all children Children born from mothers who participated in MBHMS Maternal line: NR/926 Mother report Mother-reported birth weight Child’s first-born status and sex, maternal first-born status, singleton status, birth weight, birth year, marital status, education, and adult BMI and height, and grandmother’s birth year, gestational age Table 1. Characteristics of observational epidemiologic s tudies i nvestigating grandmaternal s moking during p regnancy and h ealth o utcomes in the g randchild (continued) Study Country Study design Participants Exposure assessment Outcome assessment Confounding factors adjusted Sampling method, source No. recruited/ analyzed Rumrich 2021 [81] Finland Retrospective cohort Sampling method: general population Children born between 2005 and 2016 from mothers who were born between 1991 and 2006 in Finland Maternal line: NR/18,226 Grandmother report during pregnancy Preterm birth, low birth weight, and small body size for gestational age from the Finnish Medical Birth Register Maternal age, parity, socioeconomic status, low birth weight, preterm birth, and comorbidities during pregnancy, and grandmaternal age, parity, and socioeconomic status Shen 2020 [80] UK Prospective cohort Sampling method: all children Children born from mothers who participated in the Isle of Wight cohort study Maternal line: 472/144 Grandmother report during pregnancy Birth weight from hospital records Grandmaternal pre-pregnancy BMI and socioeconomic status, maternal smoking, birth weight and BMI at age 18 years, and gender of the child Neoplasms Azary 2016 [83] Canada, USA Case-control Sampling method: controls were selected from among friends and relatives of cases and matched by age Cases: children newly diagnosed with sporadic retinoblastoma between January 1998 to June 2011 at 11 centers; Controls: children without sporadic retinoblastoma Maternal line: Cases: unilateral 187/185; bilateral 301/286 Controls: 424/387 Mother report Doctor-diagnosed sporadic retinoblastoma from 0 to 14 years of age Child’s age, and parents’ race, education, household income, age at child’s birth, drinking and smoking Table 1. Characteristics of observational epidemiologic s tudies i nvestigating grandmaternal s moking during p regnancy and h ealth o utcomes in the g randchild (continued) Study Country Study design Participants Exposure assessment Outcome assessment Confounding factors adjusted Sampling method, source No. recruited/ analyzed Ortega-García 2010 [84] Spain Case-control Sampling method: controls were matched by child’s age, mother’s birth year and postal code Cases: children born between 2001 and 2005 newly diagnosed with cancer between 1 January, 2004 to 1 January, 2006 at one of six collaborating hospitals; Controls: children without cancer Maternal line: Cases: 128/116 Controls: 128/125 Paternal line: Cases: 128/118 Controls: 128/126 Parent report Doctor-diagnosed cancer at the mean age of 1.7 years Age, socioeconomic status, mother’s and father’s educational level, history of the familial cancer syndrome and transplacental ionizing radiation Neurodevelopmental disorders Golding 2017 [68] UK Prospective cohort Sampling method: general population Children born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992 Maternal line: 14,062/10,025 Paternal line: 14,062/NR Parent report during pregnancy Autism diagnosis identified from sources such as mother report and educational system by age 16 years Year of birth of the maternal grandmother, the ages of the grandparents when the study mother was born, the parity of the maternal grandmother, and mother’s use of social housing, education, and locus of control Table 1. Characteristics of observational epidemiologic s tudies i nvestigating grandmaternal s moking during p regnancy and h ealth o utcomes in the g randchild (continued) Study Country Study design Participants Exposure assessment Outcome assessment Confounding factors adjusted Sampling method, source No. recruited/ analyzed Golding 2020 [70] UK Prospective cohort Sampling method: general population Children born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992 Maternal line: NR/6,576 Paternal line: NR/5,393 Parent report during pregnancy Intelligence quotient assessed by trained psychologists at age 8 and 15 years Age of grandparent when parent was born, and ethnic background, education level and social class of grandparent Gustavson 2017 [75] Norway Prospective cohort Sampling method: general population Children born from all pregnant women in 1999-2008 in Norway Maternal line: NR/82,944 Mother report at 18 gestational weeks ADHD diagnosis records from the Norwegian Patient Registry at age 5–15 years Maternal and paternal age, education, and ADHD symptoms, maternal (pre-pregnancy) and paternal BMI, maternal smoking and alcohol consumption during pregnancy and parity, child’s birth year, and geographical region Pembrey 2014 [50] UK Prospective cohort Sampling method: general population Children born from all pregnant women who smoked during pregnancy in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992 Maternal line: NR/1,163 Paternal line: NR/918 Parent report during pregnancy Intelligence quotient assessed by trained psychologists at age 8 years Child’s gestational age, maternal age, parity, education, birth weight, alcohol use and housing tenure, and paternal smoking at the start of pregnancy Table 1. Characteristics of observational epidemiologic s tudies i nvestigating grandmaternal s moking during p regnancy and h ealth o utcomes in the g randchild (continued) Study Country Study design Participants Exposure assessment Outcome assessment Confounding factors adjusted Sampling method, source No. recruited/ analyzed Diseases of the visual system Williams 2019 [73] UK Prospective cohort Sampling method: general population Children born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992 Maternal line: 14,062/6,995 Paternal line: 14,062/4,099 Parent report during pregnancy Early-onset myopia assessed by study staff at age 7 years Grandparents’ birth year, ethnicity, education, age at birth of parent and social group, grandmother’s parity, and maternal vision impairments Disorders of hearing Hall 2020 [71] UK Prospective cohort Sampling method: general population Children born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992 Maternal line: 14,062/6,657 Paternal line: 14,062/4,075 Parent report during pregnancy Intolerance to loud sound determined through parental questionnaire at ages 6 and 13 years Year of birth of each grandparent, age of grandfather at birth of the parent, and ethnic origins of both grandparents Nutritional disorders Ding 2017 [49] USA Prospective cohort Sampling method: all children Children born from women who participated in Nurses’ Health Study II (the Growing Up Today Study 2) Maternal line: 10,907/6,583 Grandmother report Grandchild-reported weight and height (used for determining overweight/obesity and BMI) at age 17–22 years Grandmother’s gestational age, age at birth, level of education, consumption of alcohol, vegetable, fruit and meat, physical activity and weight gain during pregnancy, and mothers’ pre-pregnancy BMI, smoking during pregnancy, social-economic status, and diet score and physical activity during pregnancy Table 1. Characteristics of observational epidemiologic s tudies i nvestigating grandmaternal s moking during p regnancy and h ealth o utcomes in the g randchild (continued) Study Country Study design Participants Exposure assessment Outcome assessment Confounding factors adjusted Sampling method, source No. recruited/ analyzed Ding 2020 [54] USA Prospective cohort Sampling method: all children Children born from women who participated in Nurses’ Health Study II (the Growing Up Today Study 1 and 2) Maternal line: 27,805/14,001 Grandmother report Grandchild-reported weight and height (used for determining overweight/obesity and BMI) in adolescence and young adulthood Grandmother’s gestational age, age at birth, level of education, pre-pregnancy BMI, weight gain during pregnancy, diet quality score and physical activity Dougan 2016 [53] USA Prospective cohort Sampling method: all children Children born from women who participated in Nurses’ Health Study II (the Growing Up Today Study 1) Maternal line: NR/3,433 Grandmother report Grandchild-reported weight and height (used for determining overweight/obesity) at ages 12 and 17 years Grandmother’s pre-pregnancy BMI, grandmother’s age during pregnancy, grandmother’s education at time of pregnancy, and child’s age, television viewing, vigorous activity and Tanner stage of development Golding 2014 [69] UK Prospective cohort Sampling method: general population Children born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992 Maternal line: 14,062/7,352 Paternal line: 14,062/5,994 Parent report during pregnancy Weight, height, and BMI from 7 to 17 years of age, measured by study staff Parity, maternal education, paternal smoking at the start of pregnancy, and housing tenure Abbreviations: ADHD, attention deficit hyperactivity disorder; BMI, body mass index; ECRHS, the European Community Respiratory Health Survey; MBHMS, the Michigan Bone Health and Metabolism Study; NR, not reported. a Belgium, Denmark, Estonia, France, Germany, Iceland, Italy, Norway, Spain, Sweden, and United Kingdom. Figure 1. Flow diagram for study selection process Figure 2. Quality appraisal by outcome presented as percentages across all included studies Effects of grandmaternal smoking during pregnancy In maternal line, 23 unique outcomes were reported from 24 study reports [ 47 – 50 , 52 – 54 , 68 – 84 ]. We conducted meta-analyses for birth weight, body mass index (BMI) after birth, overweight/obesity, and asthma. In paternal line, 12 unique outcomes were reported from 12 reports [ 47 , 48 , 50 , 68 – 74 , 78 , 84 ], and meta-analysis was conducted for asthma. Figure 3 summarizes the effects of maternal and paternal grandmaternal smoking on categorical outcomes in the grandchild. The effects on continuous outcomes are summarized in eFigure 2 in Additional file 2. Below we describe the main results for these outcomes. The effects of grandmaternal and maternal smoking in combination are described in eResults in Additional file 2. More detailed results are available in eTables 3 and 7 in Additional file 2. Figure 3. Grandmaternal smoking during pregnancy and categorical outcomes in the grandchild A. Maternal grandmaternal smoking. B. Paternal grandmaternal smoking. The effect estimates are for grandmaternal smoking compared to non-smoking regardless of maternal smoking status during pregnancy, unless otherwise indicated. The results for asthma and overweight/obesity are from robust random-effects meta-analysis. Abbreviations: Cc, case-control study; CI, confidence interval; Co, cohort study; NA, not available. a Among grandchildren whose mothers did not smoke during pregnancy. Diseases of the respiratory system In maternal line, grandmaternal smoking was associated with a small increased risk of asthma (seven reports [ 47 , 48 , 52 , 74 , 77 , 78 , 82 ], 148,527 grandchildren, RR 1.10, 95% CI 1.02 to 1.18; Fig. 4A). In paternal line, no evidence of association was found for asthma (four reports [ 47 , 48 , 74 , 78 ], 41,069 grandchildren, RR 1.01, 95% CI 0.85 to 1.19; Fig. 4B). Figure 4. Grandmaternal smoking during pregnancy and asthma development in the grandchild A. Maternal grandmaternal smoking. B. Paternal grandmaternal smoking. Abbreviations: CI, confidence interval; cigs, cigarettes; MGM+, maternal grandmaternal smoking during pregnancy; pres, prescriptions. Disorders of newborn related to length of gestation or fetal growth In maternal line, among grandchildren whose mothers did not smoke during pregnancy, grandmaternal smoking was associated with higher birth weight (four reports [ 49 , 72 , 76 , 80 ], 19,478 grandchildren, MD (g) 40.04, 95% CI 22.60 to 57.49; eFigure 1 in Additional file 2); there was suggestive evidence that grandmaternal smoking was associated with a decreased risk of small birth weight for gestational age (one report [ 81 ], 14,558 grandchildren, RR 0.90, 95% CI 0.84 to 0.96; Fig. 3A), higher birth length (one report [ 72 ], 6,392 grandchildren, MD (cm) 0.19, 95% CI 0.02 to 0.35; eFigure 2A in Additional file 2) and higher BMI at birth (one report [ 72 ], 6,332 grandchildren, MD (g/m 2 ) 1.60, 95% CI 0.60 to 2.60; eFigure 2A in Additional file 2). No evidence of association was found for preterm birth, low birth weight, small birth length for gestational age, small head circumference for gestational age and head circumference at birth (Fig. 3A and eFigure 2A in Additional file 2). In paternal line, there was no evidence of association between grandmaternal smoking and birth weight, birth length, or BMI or head circumference at birth (eFigure 2B in Additional file 2). Neoplasms In maternal line, there was suggestive evidence that grandmaternal smoking was associated with increased risks of any cancer (one report [ 84 ], 241 grandchildren, RR 2.20, 95% CI 1.10 to 4.90; Fig. 3A) and acute lymphoblastic leukaemia (one report [ 84 ], 72 grandchildren, RR 3.00, 95% CI 1.10 to 8.80; Fig. 3A). No evidence of association was found for retinoblastoma (Fig. 3A). In paternal line, there was no evidence of association between grandmaternal smoking and cancer risk (Fig. 3B). Neurodevelopmental disorders In maternal line, there was suggestive evidence that grandmaternal smoking was associated with increased risks of ADHD (one report [ 75 ], 82,944 grandchildren, RR 1.22, 95% CI 1.09 to 1.36; Fig. 3A) and autism (one report [ 68 ], 10,025 grandchildren, RR 1.41, 95% CI 1.01 to 1.97; Fig. 3A). No evidence of association was found for IQ scores (eFigure 2A in Additional file 2). In paternal line, there was suggestive evidence that grandmaternal smoking was associated with lower IQ scores (one report [ 70 ], 5,406 grandchildren, MD -2.67, 95% CI -4.00 to -1.34; eFigure 2B in Additional file 2). Diseases of the visual system There was suggestive evidence that grandmaternal smoking was associated with a decreased risk of early-onset myopia in both maternal (one report [ 73 ], 6,995 grandchildren, RR 0.60, 95% CI 0.40 to 0.91; Fig. 3A) and paternal line (one report [ 73 ], 4,099 grandchildren, RR 0.47 95% CI 0.28 to 0.79; Fig. 3B). Disorders of hearing In paternal line, there was suggestive evidence that grandmaternal smoking was associated with a decreased risk of intolerance to loud sound (one report [ 71 ], 4,075 grandchildren, RR 0.81, 95% CI 0.65 to 0.99; Fig. 3B). No evidence of association was found in maternal line (Fig. 3A). Nutritional disorders In maternal line, there was no evidence of association between grandmaternal smoking and overweight/obesity (three reports [ 49 , 53 , 54 ], 24,017 grandchildren, RR 1.06, 95% CI 0.83 to 1.35; Fig. 3A). In both maternal and paternal line, no evidence of association was found for weight, height, and BMI after birth (eFigure 2 in Additional file 2). Subgroup analyses The subgroup results by maternal smoking status during pregnancy are presented in eFigures 3 and 4 in Additional file 2. In maternal line, the point estimates among grandchildren whose mothers smoked tended to point in an opposite direction from those among grandchildren whose mothers did not smoke for autism, birth weight, birth length, and BMI and head circumference at birth. In paternal line, a similar tendency was found for birth weight, birth length, BMI at birth, and height after birth. The subgroup results by sex of the grandchild are presented in eTables 6 and 10 in Additional file 2. In maternal line, there was suggestive evidence that the effects of grandmaternal smoking were more pronounced in boys than in girls for birth weight, birth length, BMI at birth, autism and intolerance to loud sound. In paternal line, there was suggestive evidence that the effect on early-onset myopia was more pronounced in boys than in girls. Discussion Summary of key findings In maternal line, grandmaternal smoking during pregnancy was associated with an increased risk of asthma and higher birth weight in the grandchild. There was suggestive evidence that maternal grandmaternal smoking was associated with increased risks of acute lymphoblastic leukaemia, any cancer, autism, and ADHD, decreased risks of early-onset myopia and small birth weight for gestational age, and higher birth length and BMI at birth. In paternal line, no evidence of association was found between grandmaternal smoking and asthma. There was suggestive evidence that paternal grandmaternal smoking was associated with lower IQ scores and decreased risks of early-onset myopia and intolerance to loud sound. Subgroup analyses suggested that some of the effects were more pronounced in boys than in girls. Limitations In epidemiologic studies, it is vital that confounders are identified and adjusted for in the analysis as this is fundamental to deliberations on causal inference [ 85 ]. However, identification of a sufficient set of confounders to adjust for can be particularly challenging in multigenerational studies [ 38 , 86 ]. Together with the data availability issues, the difficulty in confounder selection probably led to the inconsistency that a wide range of variables were controlled for across the included studies. In addition, the sensitivity analysis for residual confounding suggested that the results were generally not robust to potential residual confounding. Second, controversy exists that some maternal variables (e.g., smoking during pregnancy, birth weight, asthma) may in fact be potential mediators of (part of) the association between grandmaternal smoking and (some) grandchild outcomes [ 52 , 80 , 87 ]. That is, if the analytical goal is to estimate the overall causal effects of grandmaternal smoking, adjustment for these variables would be unwarranted; and if the analytical goal is to estimate the direct causal effects, adjustment for them would not reduce confounding, but rather introduce selection bias, when there are unmeasured common causes of the adjusted variables and the outcomes [ 88 ]. For example, maternal smoking during pregnancy can arguably be a mediator on a causal pathway between grandmaternal smoking and some grandchild outcomes (e.g., birth weight, asthma) (eFigure 5 in Additional file 2) [ 80 , 87 ]. Studies often stratified on or adjusted for maternal smoking during pregnancy. The interesting observation is that the point estimates for grandchild birth anthropometric measures (e.g., birth weight, birth length, BMI at birth) tended to point in an opposite direction between non-smoking and smoking mothers, suggesting that maternal smoking might qualitatively modify the effects of grandmaternal smoking on these outcomes. A similar phenomenon was reported in the so-called “birth weight paradox” [ 89 ], where studies investigated the effects of maternal smoking during pregnancy on infant mortality stratified on a potential mediator (birth weight), and found that maternal smoking was associated with higher mortality among normal-birth-weight infants, but lower mortality among low-birth-weight infants. Third, the measurement of the exposure and the confounders can be another important challenge in multigenerational studies. With the difficulty in long-term tracking of participants across generations, studies often had to rely on parental report of grandmaternal exposure and maternal proxies for grandmaternal characteristics, which is likely subject to measurement bias [ 90 ]. Fourth, for most of the outcomes, only one study existed in which multiple subgroup results were often reported. Given the potential limitations in the studies and/or multiple comparisons [ 91 ], these results are most appropriately viewed as hypothesis generation. Epigenetic inheritance It has been hypothesized that germline epigenetic inheritance may underlie the intergenerational transmission of the effects of maternal smoking during pregnancy [ 92 ]. Rat models found that perinatal nicotine exposure in F0 generation led to DNAm changes and histone modifications in the germ cells of F1 generation that will form F2 generation [ 40 , 41 ]. Human epigenome-wide association studies reported that grandmaternal smoking during pregnancy was related to differential DNAm in the grandchild [ 43 , 44 ]. In mammals, efficient epigenetic reprogramming occurs in the germline and in the early embryo to remove most of the epigenetic marks acquired during development or imposed by the environment [ 20 ]. Nevertheless, these studies provided evidence that some of the perinatal smoking/nicotine-induced epigenetic marks in F1 germ cells may escape the reprogramming and be transmitted to F2 generation. Importantly, epigenetic regulation is increasingly recognized to mediate at least in part the effects of maternal smoking during pregnancy [ 17 , 18 ]. On the other hand, experimental animal evidence exists on the intergenerational transmission of perinatal nicotine-induced asthma and neurodevelopmental disorders (e.g., ADHD, autism). Perinatal nicotine exposure in F0 rats induced an asthma-like phenotype in F2 offspring [ 40 , 42 ]. Nicotine exposure prior to and throughout breeding in F0 mice resulted in neurodevelopmental disorder-like phenotypes in F2 offspring, along with DNA hypomethylation in striatum and frontal cortex [ 93 – 95 ]. Taken together, the co-transmission of perinatal nicotine-induced epigenetic marks and some disease risks observed in rodent models as well as the potential role of epigenetic regulation in disease pathogenesis indicates that germline epigenetic inheritance may underlie the intergenerational effects. Furthermore, perinatal nicotine exposure in F0 rats could even induce gonadal DNAm changes in F2 generation as well as an asthma-like phenotype in F3 generation [ 42 , 96 ]. The potential transgenerational effects of maternal smoking during pregnancy have not been explored in epidemiologic studies. In mammals, it is generally thought that environmentally induced epigenetic changes are rarely transgenerationally inherited [ 20 , 45 ]. Future animal studies are warranted to replicate these findings and elucidate the plausibility of transgenerational inheritance of perinatal nicotine-induced epigenetic marks. Maternal smoking during pregnancy is associated with lower birth weight in the child, partly mediated through epigenetic regulation [ 2 , 21 – 26 ]. However, we found that maternal grandmaternal smoking during pregnancy was associated with higher birth weight in the grandchild. To our knowledge, no animal models exist in this regard and the potential mechanisms are yet unknown. One possible conjecture is that under in utero smoking exposure (F0), the fetal environment could modify the development of the fetus (F1) and/or its germ cells to prepare the subsequent generation (F2) for a future smoking environment [ 20 , 76 ]. Mechanistic studies are warranted to understand the potential mechanisms underlying the increased birth weight in the grandchild exposed to maternal grandmaternal smoking. Implications The degree to which the observed associations between grandmaternal smoking and grandchild outcomes reflect causal effects or are due to biases remains unclear. As discussed above, one possible explanation for the associations could be residual confounding or other biases in the design of existing studies. However, given the significant concern over the potential intergenerational transmission of the effects of maternal smoking during pregnancy, there is a need to raise public awareness that the adverse effects of smoking during pregnancy may not be limited to the exposed child, but be transmitted to the grandchild. In many countries, smoking during pregnancy remains an ongoing public health challenge [ 1 ]. There is a need to stimulate further public health efforts to enhance smoking cessation programs for pregnant women. Further longitudinal multigenerational studies across different settings are warranted to strengthen the evidence. To handle confounding, investigators should explicitly specify the causal network linking the variables under investigation using their a priori subject-matter knowledge, which can intuitively be presented in a causal diagram (e.g., directed acyclic graph (DAG)) [ 86 , 88 ]. The causal question that motivates the analytical approach should also be stated. It is worth noting that while identifying the direct causal effects of grandmaternal smoking may contribute to our understanding of the causal mechanisms for grandchild outcomes, from a public health perspective, the overall causal effects may be of greater interest [ 89 ]. Clarifying these aspects will help to provide a clearer framework for the interpretation and discussion of the results as well as for the evaluation of the proposed causal structures and analytical approaches. Further epigenetic research is needed to understand the potential role of germline epigenetic inheritance in the transmission of disease risks across generations. Conclusions Grandmaternal smoking during pregnancy, particularly from the maternal than paternal line, is a risk factor for multiple health outcomes in the grandchild, indicating a transmission of effects across generations. Germline epigenetic inheritance might explain these intergenerational effects. There is a need for further public awareness on the intergenerational adverse effects of maternal smoking during pregnancy, which should inform smoking cessation programs for pregnant women. Abbreviations ADHD, attention deficit hyperactivity disorder; BMI, body mass index; CI, confidence interval; DNAm, DNA methylation; EPHPP, the Effective Public Health Practice Project; IQ, intelligence quotient; MD, mean difference; PECOS, Population, Exposure, Comparator, Outcome, Study design; PROSPERO, the International Prospective Register of Systematic Reviews; RR, risk ratio; RVE, robust variance estimation. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Not applicable. Availability of data and materials The datasets generated and/or analysed during the current study are available in the Open Science Framework repository, https://osf.io/hav3t/?view_only=0c4f6c44aa994b0291cb7923bd5b633e . Competing interests HK reports personal fees and non-financial support from AstraZeneca, personal fees from Chiesi Pharma AB, personal fees and non-financial support from Boehringer-Ingelheim, personal fees from Novartis, personal fees from Mundipharma, personal fees and non-financial support from Orion Pharma, personal fees from SanofiGenzyme, personal fees from GlaxoSmithKline, outside the submitted work. All other authors have declared that no competing interests exist. Funding GQZ was supported by the VBG Group Herman Krefting Foundation on Asthma and Allergy, and Sahlgrenska Academy, University of Gothenburg, Sweden. BIN was supported by the VBG Group Herman Krefting Foundation on Asthma and Allergy, Knut and Alice Wallenberg Foundation, and the Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Authors’ contributions AS and BIN conceived the study. BIN performed the database searches. GQZ, YL, and BIN performed literature screening. GQZ, YL, and HHZ extracted data from the included studies and assessed study quality. GQZ performed the statistical analyses. GQZ and YL drafted the manuscript. All authors interpreted the results and critically revised the manuscript. All authors read and approved the final manuscript. Acknowledgements We would like to thank [WAITING FOR WRITTEN PERMISSION] for providing additional data, [WAITING FOR WRITTEN PERMISSION] for statistical assistance, [WAITING FOR WRITTEN PERMISSION] for initial literature screening, and [WAITING FOR WRITTEN PERMISSION] for their contributions to developing the review protocol. They were not compensated for their contribution. References Lange S, Probst C, Rehm J, Popova S. National, regional, and global prevalence of smoking during pregnancy in the general population: a systematic review and meta-analysis. Lancet Glob Health. 2018;6(7):e769–76. Pereira PP, Da Mata FA, Figueiredo AC, de Andrade KR, Pereira MG. Maternal active smoking during pregnancy and low birth weight in the Americas: a systematic review and meta-analysis. Nicotine Tob Res. 2017;19(5):497–505. Liu B, Xu G, Sun Y, Qiu X, Ryckman KK, Yu Y, et al. Maternal cigarette smoking before and during pregnancy and the risk of preterm birth: a dose-response analysis of 25 million mother-infant pairs. PLoS Med. 2020;17(8):e1003158. Shah NR, Bracken MB. A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery. Am J Obstet Gynecol. 2000;182(2):465–72. Hackshaw A, Rodeck C, Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls. Hum Reprod Update. 2011;17(5):589–604. Marufu TC, Ahankari A, Coleman T, Lewis S. Maternal smoking and the risk of still birth: systematic review and meta-analysis. BMC Public Health. 2015;15:239. Pineles BL, Hsu S, Park E, Samet JM. Systematic review and meta-analyses of perinatal death and maternal exposure to tobacco smoke during pregnancy. Am J Epidemiol. 2016;184(2):87–97. Alm B, Milerad J, Wennergren G, Skjaerven R, Oyen N, Norvenius G, et al. A case-control study of smoking and sudden infant death syndrome in the Scandinavian countries, 1992 to 1995. The Nordic Epidemiological SIDS Study. Arch Dis Child. 1998;78(4):329–34. Neuman Å, Hohmann C, Orsini N, Pershagen G, Eller E, Kjaer HF, et al. Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med. 2012;186(10):1037–43. Rayfield S, Plugge E. Systematic review and meta-analysis of the association between maternal smoking in pregnancy and childhood overweight and obesity. J Epidemiol Community Health. 2017;71(2):162–73. Banderali G, Martelli A, Landi M, Moretti F, Betti F, Radaelli G, et al. Short and long term health effects of parental tobacco smoking during pregnancy and lactation: a descriptive review. J Transl Med. 2015;13:327. Corrêa ML, Soares PSM, da Silva BGC, Wehrmeister F, Horta BL, Menezes AMB. Maternal smoking during pregnancy and intelligence quotient in offspring: a systematic review and meta-analysis. Neurotoxicology. 2021;85:99–114. Gaysina D, Fergusson DM, Leve LD, Horwood J, Reiss D, Shaw DS, et al. Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs. JAMA Psychiatry. 2013;70(9):956–63. He Y, Chen J, Zhu LH, Hua LL, Ke FF. Maternal smoking during pregnancy and ADHD: results from a systematic review and meta-analysis of prospective cohort studies. J Atten Disord. 2020;24(12):1637–47. U.S. Department of Health and Human Services. How Tobacco Smoke Causes Disease. The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2010. Rogers JM. Tobacco and pregnancy. Reprod Toxicol. 2009;28(2):152–60. Knopik VS, Marceau K, Bidwell LC, Rolan E. Prenatal substance exposure and offspring development: does DNA methylation play a role? Neurotoxicol Teratol. 2019;71:50–63. Nakamura A, François O, Lepeule J. Epigenetic alterations of maternal tobacco smoking during pregnancy: a narrative review. Int J Environ Res Public Health. 2021;18(10):5083. Kungulovski G, Jeltsch A. Epigenome editing: state of the art, concepts, and perspectives. Trends Genet. 2016;32(2):101–13. Heard E, Martienssen RA. Transgenerational epigenetic inheritance: myths and mechanisms. Cell. 2014;157(1):95–109. Küpers LK, Xu X, Jankipersadsing SA, Vaez A, la Bastide-van Gemert S, Scholtens S, et al. DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring. Int J Epidemiol. 2015;44(4):1224–1237. Morales E, Vilahur N, Salas LA, Motta V, Fernandez MF, Murcia M, et al. Genome-wide DNA methylation study in human placenta identifies novel loci associated with maternal smoking during pregnancy. Int J Epidemiol. 2016;45(5):1644–55. Witt SH, Frank J, Gilles M, Lang M, Treutlein J, Streit F, et al. Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation. BMC Genomics. 2018;19(1):290. Cardenas A, Lutz SM, Everson TM, Perron P, Bouchard L, Hivert MF. Mediation by placental DNA methylation of the association of prenatal maternal smoking and birth weight. Am J Epidemiol. 2019;188(11):1878–86. Hannon E, Schendel D, Ladd-Acosta C, Grove J, Hansen CS, Hougaard DM, et al. Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight. Philos Trans R Soc Lond B Biol Sci. 2019;374(1770):20180120. Xu R, Hong X, Zhang B, Huang W, Hou W, Wang G, et al. DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother-newborn pairs. Clin Epigenetics. 2021;13(1):47. Wilmot B, Fry R, Smeester L, Musser ED, Mill J, Nigg JT. Methylomic analysis of salivary DNA in childhood ADHD identifies altered DNA methylation in VIPR2. J Child Psychol Psychiatry. 2016;57(2):152–60. Walton E, Pingault JB, Cecil CA, Gaunt TR, Relton CL, Mill J, et al. Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study. Mol Psychiatry. 2017;22(2):250–6. van Dongen J, Zilhão NR, Sugden K, Hannon EJ, Mill J, Caspi A, et al. Epigenome-wide association study of attention-deficit/hyperactivity disorder symptoms in adults. Biol Psychiatry. 2019;86(8):599–607. Mooney MA, Ryabinin P, Wilmot B, Bhatt P, Mill J, Nigg JT. Large epigenome-wide association study of childhood ADHD identifies peripheral DNA methylation associated with disease and polygenic risk burden. Transl Psychiatry. 2020;10(1):8. Neumann A, Walton E, Alemany S, Cecil C, González JR, Jima DD, et al. Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis. Transl Psychiatry. 2020;10(1):398. Meijer M, Klein M, Hannon E, van der Meer D, Hartman C, Oosterlaan J, et al. Genome-wide DNA methylation patterns in persistent attention-deficit/hyperactivity disorder and in association with impulsive and callous traits. Front Genet. 2020;11:16. Yang IV, Pedersen BS, Liu A, O’Connor GT, Teach SJ, Kattan M, et al. DNA methylation and childhood asthma in the inner city. J Allergy Clin Immunol. 2015;136(1):69–80. Xu CJ, Söderhäll C, Bustamante M, Baïz N, Gruzieva O, Gehring U, et al. DNA methylation in childhood asthma: an epigenome-wide meta-analysis. Lancet Respir Med. 2018;6(5):379–88. Reese SE, Xu CJ, den Dekker HT, Lee MK, Sikdar S, Ruiz-Arenas C, et al. Epigenome-wide meta-analysis of DNA methylation and childhood asthma. J Allergy Clin Immunol. 2019;143(6):2062–74. Jiang Y, Forno E, Han YY, Xu Z, Hu D, Boutaoui N, et al. A genome-wide study of DNA methylation in white blood cells and asthma in Latino children and youth. Epigenetics. 2021;16(5):577–85. Hoang TT, Sikdar S, Xu CJ, Lee MK, Cardwell J, Forno E, et al. Epigenome-wide association study of DNA methylation and adult asthma in the Agricultural Lung Health Study. Eur Respir J. 2020;56(3):2000217. Mørkve Knudsen T, Rezwan FI, Jiang Y, Karmaus W, Svanes C, Holloway JW. Transgenerational and intergenerational epigenetic inheritance in allergic diseases. J Allergy Clin Immunol. 2018;142(3):765–72. Gruzieva O, Merid SK, Koppelman GH, Melén E. An update on the epigenetics of asthma. Curr Opin Allergy Clin Immunol. 2021;21(2):175–81. Rehan VK, Liu J, Naeem E, Tian J, Sakurai R, Kwong K, et al. Perinatal nicotine exposure induces asthma in second generation offspring. BMC Med. 2012;10:129. Altıntaş A, Liu J, Fabre O, Chuang TD, Wang Y, Sakurai R, et al. Perinatal exposure to nicotine alters spermatozoal DNA methylation near genes controlling nicotine action. FASEB J. 2021;35(7):e21702. Liu J, Yu C, Doherty TM, Akbari O, Allard P, Rehan VK. Perinatal nicotine exposure-induced transgenerational asthma: effects of reexposure in F1 gestation. FASEB J. 2020;34(9):11444–59. Watkins SH, Iles-Caven Y, Pembrey M, Golding J, Suderman M. Grandmaternal smoking during pregnancy is associated with differential DNA methylation in their grandchildren. BioRxiv [Preprint]. 2021 bioRxiv 440892 [posted 2021 Apr 23; cited 2021 Dec 20]. Available from: https://www.biorxiv.org/content/ 10.1101/2021.04.22.440892v1 doi:10.1101/2021.04.22.440892. Luo R, Zhang H, Mukherjee N, Karmaus W, Patil V, Arshad H, et al. Association of grandmaternal smoking during pregnancy with DNA methylation of grandchildren: the Isle of Wight study. Epigenomics. 2021;13(18):1473–83. Horsthemke B. A critical view on transgenerational epigenetic inheritance in humans. Nat Commun. 2018;9(1):2973. Perez MF, Lehner B. Intergenerational and transgenerational epigenetic inheritance in animals. Nat Cell Biol. 2019;21(2):143–51. Bråbäck L, Lodge CJ, Lowe AJ, Dharmage SC, Olsson D, Forsberg B. Childhood asthma and smoking exposures before conception-a three-generational cohort study. Pediatr Allergy Immunol. 2018;29(4):361–8. Miller LL, Henderson J, Northstone K, Pembrey M, Golding J. Do grandmaternal smoking patterns influence the etiology of childhood asthma? Chest. 2014;145(6):1213–8. Ding M, Yuan C, Gaskins AJ, Field AE, Missmer SA, Michels KB, et al. Smoking during pregnancy in relation to grandchild birth weight and BMI trajectories. PLoS ONE. 2017;12(7):e0179368. Pembrey M, Northstone K, Gregory S, Miller LL, Golding J. Is the growth of the child of a smoking mother influenced by the father's prenatal exposure to tobacco? A hypothesis generating longitudinal study. BMJ Open. 2014;4(7):e005030. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. PLoS Med. 2021;18(3):e1003583. Lodge CJ, Bråbäck L, Lowe AJ, Dharmage SC, Olsson D, Forsberg B. Grandmaternal smoking increases asthma risk in grandchildren: a nationwide Swedish cohort. Clin Exp Allergy. 2018;48(2):167–74. Dougan MM, Field AE, Rich-Edwards JW, Hankinson SE, Glynn RJ, Willett WC, et al. Is grand-parental smoking associated with adolescent obesity? A three-generational study. Int J Obes. 2016;40(3):531–7. Ding M, Strohmaier S, Schernhammer E, Yuan C, Sun Q, Michels KB, et al. Grand-maternal lifestyle during pregnancy and body mass index in adolescence and young adulthood: an intergenerational cohort study. Sci Rep. 2020;10(1):14432. World Health Organization. International Classification of Diseases, 11th Revision [cited 01 November 2021]. Available from: https://icd.who.int/browse11/l-m/en . Quality Assessment Tool for Quantitative Studies [cited 13 July 2021]. Available from: https://www.ephpp.ca/quality-assessment-tool-for-quantitative-studies/ . Zhang GQ, Chen JL, Luo Y, Mathur MB, Anagnostis P, Nurmatov U, et al. Menopausal hormone therapy and women's health: an umbrella review. PLoS Med. 2021;18(8):e1003731. Hedges LV, Tipton E, Johnson MC. Robust variance estimation in meta-regression with dependent effect size estimates. Res Synth Methods. 2010;1(1):39–65. Tipton E. Small sample adjustments for robust variance estimation with meta-regression. Psychol Methods. 2015;20(3):375–93. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539–58. Rücker G, Schwarzer G, Carpenter JR, Schumacher M. Undue reliance on I 2 in assessing heterogeneity may mislead. BMC Med Res Methodol. 2008;8:79. Mathur MB, VanderWeele TJ. Sensitivity analysis for publication bias in meta-analyses. J R Stat Soc Ser C Appl Stat. 2020;69(5):1091–119. VanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167(4):268–74. Mathur MB, VanderWeele TJ. Sensitivity analysis for unmeasured confounding in meta-analyses. J Am Stat Assoc. 2020;115(529):163–72. Mathur MB, Ding P, Riddell CA, VanderWeele TJ. Website and R package for computing E-values. Epidemiology. 2018;29(5):e45–7. VanderWeele TJ. Optimal approximate conversions of odds ratios and hazard ratios to risk ratios. Biometrics. 2020;76(3):746–52. R Core Team. (2021). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/ . Golding J, Ellis G, Gregory S, Birmingham K, Iles-Caven Y, Rai D, et al. Grand-maternal smoking in pregnancy and grandchild's autistic traits and diagnosed autism. Sci Rep. 2017;7:46179. Golding J, Northstone K, Gregory S, Miller LL, Pembrey M. The anthropometry of children and adolescents may be influenced by the prenatal smoking habits of their grandmothers: a longitudinal cohort study. Am J Hum Biol. 2014;26(6):731–9. Golding J, van den Berg G, Northstone K, Suderman M, Ellis G, Iles-Caven Y, et al. Grandchild's IQ is associated with grandparental environments prior to the birth of the parents. Wellcome Open Res. 2020;5:198. Hall A, Northstone K, Iles-Caven Y, Ellis G, Gregory S, Golding J, et al. Intolerance of loud sounds in childhood: is there an intergenerational association with grandmaternal smoking in pregnancy? PLoS ONE. 2020;15(2):e0229323. Miller LL, Pembrey M, Davey Smith G, Northstone K, Golding J. Is the growth of the fetus of a non-smoking mother influenced by the smoking of either grandmother while pregnant? PLoS ONE. 2014;9(2):e86781. Williams C, Suderman M, Guggenheim JA, Ellis G, Gregory S, Iles-Caven Y, et al. Grandmothers' smoking in pregnancy is associated with a reduced prevalence of early-onset myopia. Sci Rep. 2019;9(1):15413. Accordini S, Calciano L, Johannessen A, Portas L, Benediktsdóttir B, Bertelsen RJ, et al. A three-generation study on the association of tobacco smoking with asthma. Int J Epidemiol. 2018;47(4):1106–17. Gustavson K, Ystrom E, Stoltenberg C, Susser E, Surén P, Magnus P, et al. Smoking in pregnancy and child ADHD. Pediatrics. 2017;139(2):e20162509. Hyppönen E, Smith GD, Power C. Effects of grandmothers' smoking in pregnancy on birth weight: intergenerational cohort study. BMJ. 2003;327(7420):898. Magnus MC, Håberg SE, Karlstad Ø, Nafstad P, London SJ, Nystad W. Grandmother's smoking when pregnant with the mother and asthma in the grandchild: the Norwegian Mother and Child Cohort Study. Thorax. 2015;70(3):237–43. Mahon GM, Koppelman GH, Vonk JM. Grandmaternal smoking, asthma and lung function in the offspring: the Lifelines cohort study. Thorax. 2021;76(5):441–7. Rillamas-Sun E, Harlow SD, Randolph JF Jr. Grandmothers' smoking in pregnancy and grandchildren's birth weight: comparisons by grandmother birth cohort. Matern Child Health J. 2014;18(7):1691–8. Shen Y, Zhang H, Jiang Y, Mzayek F, Arshad H, Karmaus W. Maternal birth weight and BMI mediate the transgenerational effect of grandmaternal BMI on grandchild's birth weight. Obesity. 2020;28(3):647–54. Rumrich IK, Hänninen O, Viluksela M, Vähäkangas K. Effect of grandmaternal smoking on body size and proportions at birth. Int J Environ Res Public Health. 2021;18(9):4985. Li YF, Langholz B, Salam MT, Gilliland FD. Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest. 2005;127(4):1232–41. Azary S, Ganguly A, Bunin GR, Lombardi C, Park AS, Ritz B, et al. Sporadic retinoblastoma and parental smoking and alcohol consumption before and after conception: a report from the Children's Oncology Group. PLoS ONE. 2016;11(3):e0151728. Ortega-García JA, Martin M, López-Fernández MT, Fuster-Soler JL, Donat-Colomer J, López-Ibor B, et al. Transgenerational tobacco smoke exposure and childhood cancer: an observational study. J Paediatr Child Health. 2010;46(6):291–5. Hernán MA, Robins JM. Observational studies. In: Hernán MA, Robins JM, editors. Causal Inference: What If. Boca Raton: Chapman & Hall/CRC; 2020. pp. 25–37. Hernán MA, Robins JM. Confounding. In: Hernán MA, Robins JM, editors. Causal Inference: What If. Boca Raton: Chapman & Hall/CRC; 2020. pp. 83–94. Arshad SH, Karmaus W, Zhang H, Holloway JW. Multigenerational cohorts in patients with asthma and allergy. J Allergy Clin Immunol. 2017;139(2):415–21. Hernán MA, Hernández-Díaz S, Werler MM, Mitchell AA. Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol. 2002;155(2):176–84. Hernández-Díaz S, Schisterman EF, Hernán MA. The birth weight "paradox". uncovered? Am J Epidemiol. 2006;164(11):1115–20. Hernán MA, Robins JM. Measurement bias. In: Hernán MA, Robins JM, editors. Causal Inference: What If. Boca Raton: Chapman & Hall/CRC; 2020. pp. 113–9. Sun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ. 2010;340:c117. Breton CV, Landon R, Kahn LG, Enlow MB, Peterson AK, Bastain T, et al. Exploring the evidence for epigenetic regulation of environmental influences on child health across generations. Commun Biol. 2021;4(1):769. Buck JM, Sanders KN, Wageman CR, Knopik VS, Stitzel JA, O'Neill HC. Developmental nicotine exposure precipitates multigenerational maternal transmission of nicotine preference and ADHD-like behavioral, rhythmometric, neuropharmacological, and epigenetic anomalies in adolescent mice. Neuropharmacology. 2019;149:66–82. Buck JM, O'Neill HC, Stitzel JA. Developmental nicotine exposure elicits multigenerational disequilibria in proBDNF proteolysis and glucocorticoid signaling in the frontal cortices, striata, and hippocampi of adolescent mice. Biochem Pharmacol. 2019;168:438–51. Buck JM, O'Neill HC, Stitzel JA. Developmental nicotine exposure engenders intergenerational downregulation and aberrant posttranslational modification of cardinal epigenetic factors in the frontal cortices, striata, and hippocampi of adolescent mice. Epigenetics Chromatin. 2020;13(1):13. Rehan VK, Liu J, Sakurai R, Torday JS. Perinatal nicotine-induced transgenerational asthma. Am J Physiol Lung Cell Mol Physiol. 2013;305(7):L501–7. Supplementary Files Additionalfile1.docx Additional file 1. PRISMA checklist. (docx) Additionalfile2.docx Additional file 2. Excluded studies, quality assessment, and analysis results (heterogeneity, publication bias, residual confounding, etc.). (docx) Additionalfile3.docx Additional file 3. Statistical analysis protocol. (docx) Additionalfile4.pdf Additional file 4. R scripts for meta-analyses of observational epidemiologic studies. (pdf) Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1625650","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":103841262,"identity":"a7baded3-c0dc-43fb-bc84-9e10bcc8365d","order_by":0,"name":"Guo-Qiang Zhang","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-8785-8717","institution":"University of Gothenburg","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Guo-Qiang","middleName":"","lastName":"Zhang","suffix":""},{"id":103841263,"identity":"66122cab-4f61-40aa-88e1-1413f043fb41","order_by":1,"name":"Ying Luo","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Ying","middleName":"","lastName":"Luo","suffix":""},{"id":103841264,"identity":"65a4808a-239f-4ada-9799-d3d54eade181","order_by":2,"name":"Hui-Hua Zhang","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Hui-Hua","middleName":"","lastName":"Zhang","suffix":""},{"id":103841265,"identity":"dcd03f1d-578c-4468-923f-d440581af6f8","order_by":3,"name":"Zhong-Yue Li","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Zhong-Yue","middleName":"","lastName":"Li","suffix":""},{"id":103841266,"identity":"3e19abdb-1dfe-4a10-a1d4-c86a4f4db3af","order_by":4,"name":"Hannu 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Nwaru","email":"","orcid":"","institution":"","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bright","middleName":"","lastName":"Nwaru","suffix":""}],"badges":[],"createdAt":"2022-05-05 11:04:26","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-1625650/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-1625650/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":21156822,"identity":"5f107f7c-0b4e-4503-9460-06dea60104d4","added_by":"auto","created_at":"2022-05-06 13:50:11","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":83754,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFlow diagram for study selection process\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"OnlineFigure1.png","url":"https://assets-eu.researchsquare.com/files/rs-1625650/v1/cad7c20e57066ac7ced6c94a.png"},{"id":21156427,"identity":"81d4e9ee-a66f-40c9-8882-38e33ff37ef9","added_by":"auto","created_at":"2022-05-06 13:40:11","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":30131,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eQuality appraisal by outcome presented as percentages across all included studies\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"OnlineFigure2.png","url":"https://assets-eu.researchsquare.com/files/rs-1625650/v1/32a80f65ecdd02d458b846dd.png"},{"id":21156823,"identity":"0df0aba5-ef53-4380-82e2-26dde70feff1","added_by":"auto","created_at":"2022-05-06 13:50:11","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":79162,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGrandmaternal smoking during pregnancy and categorical outcomes in the grandchild\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA. Maternal grandmaternal smoking. B. Paternal grandmaternal smoking. The effect estimates are for grandmaternal smoking compared to non-smoking regardless of maternal smoking status during pregnancy, unless otherwise indicated. The results for asthma and overweight/obesity are from robust random-effects meta-analysis. Abbreviations: Cc, case-control study; CI, confidence interval; Co, cohort study; NA, not available.\u003c/p\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003e Among grandchildren whose mothers did not smoke during pregnancy.\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1625650/v1/27cacd6bfd9d81751185ed19.jpg"},{"id":21156666,"identity":"02d2e7a1-9153-4250-b76f-c08f53e19249","added_by":"auto","created_at":"2022-05-06 13:45:11","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":71311,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGrandmaternal smoking during pregnancy and asthma development in the grandchild\u003c/strong\u003e\u003c/p\u003e\u003cp\u003eA. Maternal grandmaternal smoking. B. Paternal grandmaternal smoking. Abbreviations: CI, confidence interval; cigs, cigarettes; MGM+, maternal grandmaternal smoking during pregnancy; pres, prescriptions.\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1625650/v1/eb97dac1cb821128a9ef84fd.jpg"},{"id":38480594,"identity":"e0c83d22-9f7f-4e26-ba53-fc4238c4867b","added_by":"auto","created_at":"2023-06-13 15:24:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1766163,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1625650/v1/69f737be-043f-4ce6-863d-dcb208e1645a.pdf"},{"id":21156430,"identity":"2a8502eb-97a5-4fd7-a272-6f254fcd3457","added_by":"auto","created_at":"2022-05-06 13:40:11","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":34709,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 1. \u003c/strong\u003ePRISMA checklist. (docx)\u003c/p\u003e","description":"","filename":"Additionalfile1.docx","url":"https://assets-eu.researchsquare.com/files/rs-1625650/v1/dcd606ca03830a121730c5df.docx"},{"id":21156433,"identity":"221b137f-4a56-4027-9147-f4a885ef472a","added_by":"auto","created_at":"2022-05-06 13:40:11","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":5051406,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 2. \u003c/strong\u003eExcluded studies, quality assessment, and analysis results (heterogeneity, publication bias, residual confounding, etc.). (docx)\u003c/p\u003e","description":"","filename":"Additionalfile2.docx","url":"https://assets-eu.researchsquare.com/files/rs-1625650/v1/82c7bd85b5cbfa1f3021474f.docx"},{"id":21156431,"identity":"65abae17-59b9-4876-8fc3-25f1fe5ff4d2","added_by":"auto","created_at":"2022-05-06 13:40:11","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":33539,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 3. \u003c/strong\u003eStatistical analysis protocol. (docx)\u003c/p\u003e","description":"","filename":"Additionalfile3.docx","url":"https://assets-eu.researchsquare.com/files/rs-1625650/v1/65628e14837ed65249e4b1c0.docx"},{"id":21156669,"identity":"ccb9895f-782b-4fa3-9634-af45c8378fa9","added_by":"auto","created_at":"2022-05-06 13:45:11","extension":"pdf","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":70526,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eAdditional file 4. \u003c/strong\u003eR scripts for meta-analyses of observational epidemiologic studies. (pdf)\u003c/p\u003e","description":"","filename":"Additionalfile4.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1625650/v1/aef792bc1b6f0f6ff2c4dc1b.pdf"}],"financialInterests":"","formattedTitle":"Grandmaternal smoking during pregnancy and grandchild health: A systematic review and meta-analysis","fulltext":[{"header":"Background","content":"\u003cp\u003eGlobally, the prevalence of maternal smoking during pregnancy is estimated to be around 2% [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. However, in many countries, smoking during pregnancy is still common. More than 10% of pregnant women smoked during pregnancy in 29 (17%) of 174 countries and more than 20% in 12 (7%) countries [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Specifically, the prevalence of smoking during pregnancy was on average 8% in Europe (ranging from 0.5\u0026ndash;38%) and 17% in the USA [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Notably, more than 70% of pregnant women who smoked during pregnancy smoked daily rather than occasionally [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. With decades of research, smoking during pregnancy has been linked to a host of detrimental effects on the exposed child. For example, smoking during pregnancy is associated perinatally with low birth weight [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e], preterm birth [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], various birth defects [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e], still birth [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], and neonatal death [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]; and postnatally with sudden infant death syndrome [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], asthma [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], obesity [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], high blood pressure [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], low intelligence quotient (IQ) scores [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], conduct problems [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], and attention deficit hyperactivity disorder (ADHD) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. These findings suggest that smoking during pregnancy may affect offspring\u0026rsquo;s health already \u003cem\u003ein utero\u003c/em\u003e, with potentially life-long negative health consequences.\u003c/p\u003e \u003cp\u003eThe biologic mechanisms by which maternal smoking may lead to diverse adverse health in the offspring are complex. Extensive human and laboratory studies have shown that cigarette smoke contains more than 7,000 chemicals, many of which (e.g., nicotine, carbon monoxide) can cross the placental barrier to influence fetal programming or have a direct toxicologic effect on the fetus [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. In recent years, it is increasingly recognized that many of the mechanisms are mediated epigenetically [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. The epigenome refers to the biochemical information that lies \u0026lsquo;over and above\u0026rsquo; the DNA sequence and regulates the expression of genes through mechanisms such as DNA methylation (DNAm), histone modifications and non-coding RNAs [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. There is a growing body of literature that smoking during pregnancy is associated with numerous epigenetic alterations in the exposed child, which may in turn affect health outcomes [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. For example, many studies consistently found that DNAm at specific gene loci mediated in part the relationship between maternal smoking and offspring low birth weight [\u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. An increasing number of human epigenome-wide association studies showed that DNAm marks at some specific gene regions were associated with ADHD and asthma, suggesting that epigenetic mechanisms may play an important role in their etiology [\u003cspan additionalcitationids=\"CR28 CR29 CR30 CR31 CR32 CR33 CR34 CR35 CR36 CR37 CR38\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e]. In rat models, maternal nicotine exposure during pregnancy (F0) induced epigenetic changes not only in the first generation (F1), but also in the germ cells of F1 generation that form the second generation (F2) (termed as intergenerational epigenetic inheritance) and of F2 generation that form the third generation (F3) (as transgenerational epigenetic inheritance) [\u003cspan additionalcitationids=\"CR41\" citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Furthermore, recent human epigenome-wide association studies found that grandmaternal smoking during pregnancy was associated with differential DNAm in the grandchild [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWhile the detrimental health effects of smoking during pregnancy on the exposed child are well established, it is unclear whether these effects are transmitted to the subsequent generation(s) through epigenetic inheritance. Whilst the plausibility of epigenetic inheritance is being elucidated [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e, \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e], a number of epidemiologic intergenerational studies have investigated the impact of grandmaternal smoking during pregnancy on various health outcomes in the grandchild, but results are inconsistent for some outcomes (e.g., birth weight, asthma) [\u003cspan additionalcitationids=\"CR48 CR49\" citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e]. To elucidate the underlying evidence, we undertook a systematic review of observational epidemiologic studies investigating the association between grandmaternal smoking during pregnancy and multiple health outcomes in the grandchild. We sought to comprehensively summarize the available evidence on the potential intergenerational transmission of the effects of maternal smoking during pregnancy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe protocol for this systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) (CRD42017084039). This study was reported as per the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guideline [\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e] (Additional file 1). Ethical approval was not required for this study.\u003c/p\u003e \u003cp\u003e \u003cb\u003eLiterature search and eligibility criteria\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe searched MEDLINE, EMBASE, Cochrane Library, ISI Web of Science, CINAHL, Google Scholar, Scopus, Global Health, PsycINFO, Zetoc, CAB International and WHO Global Health Library from inception to March 02, 2021. The database search was updated on October 18, 2021. No language restriction was applied. The search strategies are available in the PROSPERO protocol. Three investigators (GQZ, YL and HHZ) independently screened the titles and/or abstracts and reviewed full-text articles for eligibility. Any discrepancies were resolved by discussion or by a third investigator (BIN). We also manually checked the references of included studies and relevant reviews to identify additional eligible studies.\u003c/p\u003e \u003cp\u003eStudies were selected for inclusion if they met the following Population, Exposure, Comparator, Outcome, Study design (PECOS) criteria: 1) Population: grandmother-mother/father-child triads of any ethnicity in any country or setting; 2) Exposure: maternal grandmaternal smoking during pregnancy (i.e., grandmother smoked any amount of cigarettes when pregnant with the mother) or paternal grandmaternal smoking during pregnancy (i.e., grandmother smoked any amount of cigarettes when pregnant with the father); 3) Comparator: no maternal or paternal grandmaternal smoking during pregnancy; 4) Outcome: any health outcome in the grandchild of any age; 5) Study design: analytic epidemiologic studies (prospective or retrospective cohort and case-control design). We also included studies investigating the effects of both grandmaternal and maternal smoking during pregnancy relative to neither of them smoked during pregnancy. We excluded reviews, commentaries, studies of grandmaternal smoking not during pregnancy, and studies of indirect outcome measures (e.g., DNAm, dietary inflammatory index, lung function parameters). For conference abstracts, corresponding authors were contacted to request additional data. If no information was provided, they were excluded from our review (eTable 1 in Additional file 2).\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData extraction and quality assessment\u003c/h2\u003e \u003cp\u003eThree investigators (GQZ, YL and HHZ) independently extracted data by outcome using a customized data extraction form. For each article, we extracted first author, year of publication, country, study design, exposure group, reference group, sex and age of the grandchild, outcome examined, number of cases and controls in case-control studies or total population in cohort studies for binary outcomes, number of total population in cohort studies for continuous outcomes, type of effect measure (mean difference (MD), risk ratio (RR), odds ratio or hazard ratio), and maximally-adjusted effect estimate with 95% confidence interval (CI). When studies reported multiple effect estimates for different exposure levels relative to non-smoking [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e], or estimates relative to a reference group other than non-smoking [\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e], corresponding authors were contacted to obtain the estimates comparing smoking versus non-smoking. We received the requested data from three studies [\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e, \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e, \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e]. We categorized outcomes according to the International Classification of Diseases 11th Revision (ICD-11) [\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e55\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThree investigators (GQZ, YL and HHZ) independently assessed the risk of bias of included studies by outcome using the Effective Public Health Practice Project (EPHPP) tool [\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e56\u003c/span\u003e]. The EPHPP tool consists of six domains: study design, selection bias, confounders, exposure measurement, outcome measurement and statistical analysis. Each domain is rated as strong, moderate, or weak. Disagreements during data extraction and quality assessment were resolved by discussion or by a third investigator (BIN).\u003c/p\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eData synthesis and analysis\u003c/h2\u003e \u003cp\u003eWe developed \u003cem\u003ea priori\u003c/em\u003e an analysis protocol for this review (Additional file 3), which was adapted from our earlier work [\u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e57\u003c/span\u003e]. We used the random-effects robust variance estimation (RVE) method to calculate the summary average effect and its 95% CI [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e]. The RVE method does not require any distributional assumptions on the population effects, can accommodate dependence among effect estimates (e.g., multiple estimates based on the same individuals at different time points, or computed using a common control group), and can provide correct inference even in meta-analyses with a small number of studies [\u003cspan citationid=\"CR58\" class=\"CitationRef\"\u003e58\u003c/span\u003e, \u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e59\u003c/span\u003e]. We quantified the extent of heterogeneity by estimating the standard deviation of population effects [\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e60\u003c/span\u003e, \u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e61\u003c/span\u003e]. To evaluate the robustness of meta-analysis results to potential publication bias, we calculated the S-value [\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e62\u003c/span\u003e], which represents the severity of publication bias that would hypothetically be required to shift the summary estimate to the null. For binary outcomes, we also calculated the E-value [\u003cspan additionalcitationids=\"CR64\" citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e65\u003c/span\u003e], which assesses how strong residual confounding would have to be to \u0026ldquo;explain away\u0026rdquo; an observed exposure-outcome association.\u003c/p\u003e \u003cp\u003eThe primary analyses focused on the average effects of grandmaternal smoking during pregnancy. These analyses were conducted separately for maternal and paternal line. Subgroup analyses were conducted according to maternal smoking status during pregnancy (smoking versus non-smoking) and sex of the grandchild (boys versus girls). We also conducted analyses for the effects of grandmaternal and maternal smoking during pregnancy in combination compared to neither of them smoked during pregnancy. For binary outcomes, all estimates were converted to the RR scale [\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e63\u003c/span\u003e, \u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e66\u003c/span\u003e], and results were presented on that scale. All statistical analyses were performed using R software (version 4.0.4) [\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e67\u003c/span\u003e]. The R scripts and datasets are respectively available in Additional file 4 and at the Open Science Framework.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec6\"\u003e\n \u003ch2\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eCharacteristics of included studies\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eOverall, we identified 1,152 records, scrutinized 49 full-text articles, and ultimately included 24 reports from 15 unique studies, including 18 reports from nine prospective cohort studies [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e48\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026ndash;\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e50\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e53\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e54\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e68\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026ndash;\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e80\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], three reports from three retrospective cohort studies [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e47\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e52\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e81\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], one report from one nested case-control study [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e82\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], and two reports from two case-control studies [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e83\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e84\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e]. These reports were published between 2003 and 2021. Figure 1 shows the study selection process. Studies excluded at the full-text screening stage with reasons for their exclusion are available in eTable 1 in Additional file 2. Characteristics of the included studies are summarized in Table\u0026nbsp;\u003c/span\u003e\u003cspan class=\"InternalRef\" style=\"color: rgb(0, 0, 0);\"\u003e1\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e. Figure 2 presents a summary of quality assessment by outcome across all included studies. Each EPHPP domain judgment for each outcome is available in eTable 2 in Additional file 2.\u003c/span\u003e\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/div\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eTable 1. Characteristics of\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eobservational epidemiologic s\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003etudies\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ei\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003envestigating\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003egrandmaternal\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003es\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003emoking during\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ep\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eregnancy and\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eh\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eealth\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eo\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eutcomes in the\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eg\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003erandchild\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003ctable style=\"width: 100%;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.12%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.18%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eCountry\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.14%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy design\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:24.86%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eParticipants\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.2%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eExposure assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:13.8%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eOutcome assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:22.7%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eConfounding factors adjusted\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:13.82%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eSampling method, source\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:11.04%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNo. recruited/\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eanalyzed\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width:100.0%;border:none;border-bottom: solid windowtext 1.0pt;background: #BFBFBF;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eDiseases of the respiratory system\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eAccordini 2018 [74]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eEurope\u003csup\u003ea\u003c/sup\u003e, Australia\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: all children\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from parents who participated in the ECRHS I and III\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e5,002/4,666\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e4,563/4,192\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report at ECRHS I\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent-reported ever asthma with or without nasal allergies in children aged 0\u0026ndash;51 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother\u0026rsquo;s and grandfather\u0026rsquo;s ever asthma and education level, maternal and paternal ever asthma, age, smoking and education level, and offspring\u0026rsquo;s gender and age\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eBr\u0026aring;b\u0026auml;ck 2018 [47]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSweden\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eRetrospective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born after June 31, 2005, from all mothers born between 1982-1986 in Sweden\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e15,265/10,329\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e15,265/10,329\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother report at gestational week 8-12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePurchase of any asthma medication (inhaled steroid and/or leukotriene antagonist) by age 6 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal smoking habits, maternal and paternal grandmother\u0026rsquo;s age, level of education, social welfare, BMI and asthma medication, maternal and paternal grandfather\u0026rsquo;s asthma medication, maternal and paternal age, sex of the child, and county of residence at mother\u0026rsquo;s and father\u0026rsquo;s birth\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eLi 2005 [82]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUSA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNested case-control\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: controls were countermatched on \u003cem\u003ein utero\u003c/em\u003e exposure to maternal smoking within grade, sex, and community of residence\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCases: asthmatic children from public schools (grades 4, 7, 10) in 12 southern California communities in 1993;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eControls: non-asthmatic children from the same cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCases: 338/235\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eControls: 570/335\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMother report\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent-reported doctor-diagnosed asthma in the first 5 years of life\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrade, sex, community of residence, race/ethnicity, gestational age, and secondhand smoke exposure\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\u003cspan style=\"font-size: 16px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eTable 1. Characteristics of\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eobservational epidemiologic s\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003etudies\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ei\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003envestigating\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003egrandmaternal\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003es\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003emoking during\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ep\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eregnancy and\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eh\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eealth\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eo\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eutcomes in the\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eg\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003erandchild\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;(continued)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003ctable style=\"width: 100%;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.12%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.18%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eCountry\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.14%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy design\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:24.86%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eParticipants\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.2%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eExposure assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:13.8%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eOutcome assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:22.7%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eConfounding factors adjusted\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:13.82%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eSampling method, source\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:11.04%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNo. recruited/\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eanalyzed\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eLodge 2018 [52]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSweden\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eRetrospective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born between 1996-2010, from all mothers born between 1982-1986 in Sweden\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e81,550/48,971\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother report at gestational week 10-12\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePurchase of any asthma medication (beta agonist, inhaled steroid, or leukotriene antagonist) by age 6 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChild\u0026rsquo;s gender and birth order, maternal nicotine exposure (smoking and snus), mother\u0026rsquo;s years of education, family allowance, birth order, residence at childbirth, and age, grandmother\u0026rsquo;s residence at childbirth, years of education, social allowance, asthma, age and BMI, and proxy for grandfather\u0026rsquo;s smoking\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMagnus 2015 [77]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNorway\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women in 1999-2008 in Norway\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e110,291/46,564\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMother report at 18 gestational weeks\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCurrent asthma at age 3 and 7 years based on mother-reported asthma diagnosis/symptoms and/or dispensed asthma medications\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal age, parity, education, salary, pre-pregnancy BMI, asthma and smoking during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMahon 2021 [78]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eThe Netherlands\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: all children\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren whose parents participated in the LifeLines Cohort Study\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e167,548/30,546\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e167,548/20,923\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandchild- or parent-reported asthma from 4 to 50 years of age\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGender, maternal smoking, current or former smoking, passive environmental smoke exposure\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ein childhood, maternal age, birth weight, gestational age, breast feeding and socioeconomic status\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMiller 2014 [48]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/6,881\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/5,625\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMother-reported doctor-diagnosed asthma ever at age 7 to 8 years in association with a history of wheezing in the preceding 12 months\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eFamily history of asthma, gestation, parity, maternal education, breastfeeding, the amount the mother smoked during pregnancy, paternal smoking in pregnancy and exposure of the child to environmental tobacco smoke\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\u003cspan style=\"font-size: 16px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eTable 1. Characteristics of\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eobservational epidemiologic s\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003etudies\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ei\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003envestigating\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003egrandmaternal\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003es\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003emoking during\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ep\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eregnancy and\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eh\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eealth\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eo\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eutcomes in the\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eg\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003erandchild\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;(continued)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003ctable style=\"width: 100%;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.12%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.18%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eCountry\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.14%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy design\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:24.86%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eParticipants\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.2%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eExposure assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:13.8%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eOutcome assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:22.7%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eConfounding factors adjusted\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:13.82%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eSampling method, source\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:11.04%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNo. recruited/\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eanalyzed\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width:100.0%;border:none;border-bottom: solid windowtext 1.0pt;background: #BFBFBF;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eDisorders of newborn related to length of gestation or fetal growth\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eDing 2017 [49]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUSA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: all children\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from women who participated in Nurses\u0026rsquo; Health Study II (the Growing Up Today Study 2)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e10,907/5,759\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother report\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMother-reported birth weight\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother\u0026rsquo;s gestational age, age at birth, level of education, consumption of alcohol, vegetable, fruit and meat, physical activity and weight gain during pregnancy, and mothers\u0026rsquo; pre-pregnancy BMI, smoking during pregnancy, social-economic status, and diet score and physical activity during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGustavson 2017 [75]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNorway\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women in 1999-2008 in Norway\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/82,550\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMother report at 18 gestational weeks\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eBirth weight records from the Medical Birth Registry of Norway\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal and paternal age, education, and ADHD symptoms, maternal (pre-pregnancy) and paternal BMI, maternal smoking and alcohol consumption during pregnancy and parity, child\u0026rsquo;s birth year, and geographical region\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eHypp\u0026ouml;nen 2003 [76]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all mothers who were born from 3 to 9 March 1958 in England, Scotland, and Wales\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/9,028\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother report\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMother-reported birth weight\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChild\u0026rsquo;s gestational age, sex and birth order, and maternal smoking, height, BMI, and birth weight\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\u003cspan style=\"font-size: 16px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eTable 1. Characteristics of\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eobservational epidemiologic s\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003etudies\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ei\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003envestigating\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003egrandmaternal\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003es\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003emoking during\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ep\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eregnancy and\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eh\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eealth\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eo\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eutcomes in the\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eg\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003erandchild\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;(continued)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003ctable style=\"width: 100%;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.12%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.18%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eCountry\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.14%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy design\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:24.86%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eParticipants\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.2%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eExposure assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:13.8%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eOutcome assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:22.7%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eConfounding factors adjusted\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:13.82%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eSampling method, source\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:11.04%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNo. recruited/\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eanalyzed\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMiller 2014 [72]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women who did not smoke during pregnancy in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/8,188\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/6,773\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eBirth weight, birth length, head circumference and BMI, measured by study staff\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChild\u0026rsquo;s gestational age, maternal age, parity, education, birth weight, alcohol use and housing tenure, and paternal smoking at the start of pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePembrey 2014 [50]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women who smoked during pregnancy in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/3,502\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/2,354\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eBirth weight, birth length, head circumference and BMI, measured by study staff\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChild\u0026rsquo;s gestational age, maternal age, parity, education, birth weight, alcohol use and housing tenure, and paternal smoking at the start of pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eRillamas-Sun 2014 [79]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUSA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: all children\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from mothers who participated in MBHMS\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line: NR/926\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMother report\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMother-reported birth weight\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChild\u0026rsquo;s first-born status and sex, maternal first-born status, singleton status, birth weight, birth year, marital status, education, and adult BMI and height, and grandmother\u0026rsquo;s birth year, gestational age\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\u003cspan style=\"font-size: 16px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eTable 1. Characteristics of\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eobservational epidemiologic s\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003etudies\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ei\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003envestigating\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003egrandmaternal\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003es\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003emoking during\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ep\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eregnancy and\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eh\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eealth\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eo\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eutcomes in the\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eg\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003erandchild\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;(continued)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003ctable style=\"width: 100%;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.12%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.18%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eCountry\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.14%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy design\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:24.86%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eParticipants\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.2%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eExposure assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:13.8%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eOutcome assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:22.7%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eConfounding factors adjusted\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:13.82%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eSampling method, source\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:11.04%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNo. recruited/\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eanalyzed\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eRumrich 2021 [81]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eFinland\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eRetrospective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born between 2005 and 2016 from mothers who were born between 1991 and 2006 in Finland\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/18,226\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePreterm birth, low birth weight, and small body size for gestational age from the Finnish Medical Birth Register\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal age, parity, socioeconomic status, low birth weight, preterm birth, and comorbidities during pregnancy, and grandmaternal age, parity, and socioeconomic status\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eShen 2020 [80]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: all children\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from mothers who participated in the Isle of Wight cohort study\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e472/144\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eBirth weight from hospital records\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmaternal pre-pregnancy BMI and socioeconomic status, maternal smoking, birth weight and BMI at age 18 years, and gender of the child\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width:100.0%;border:none;border-bottom: solid windowtext 1.0pt;background: #BFBFBF;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNeoplasms\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eAzary 2016 [83]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCanada, USA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCase-control\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: controls were selected from among friends and relatives of cases and matched by age\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCases: children newly diagnosed with sporadic retinoblastoma between January 1998 to June 2011 at 11 centers;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eControls: children without sporadic retinoblastoma\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCases: unilateral 187/185; bilateral 301/286\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eControls: 424/387\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMother report\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eDoctor-diagnosed sporadic retinoblastoma from 0 to 14 years of age\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChild\u0026rsquo;s age, and parents\u0026rsquo; race, education, household income, age at child\u0026rsquo;s birth, drinking and smoking\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\u003cspan style=\"font-size: 16px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eTable 1. Characteristics of\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eobservational epidemiologic s\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003etudies\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ei\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003envestigating\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003egrandmaternal\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003es\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003emoking during\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ep\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eregnancy and\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eh\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eealth\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eo\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eutcomes in the\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eg\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003erandchild\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;(continued)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003ctable style=\"width: 100%;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.12%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.18%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eCountry\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.14%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy design\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:24.86%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eParticipants\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.2%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eExposure assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:13.8%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eOutcome assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:22.7%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eConfounding factors adjusted\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:13.82%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eSampling method, source\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:11.04%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNo. recruited/\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eanalyzed\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eOrtega-Garc\u0026iacute;a 2010 [84]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSpain\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCase-control\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: controls were matched by child\u0026rsquo;s age, mother\u0026rsquo;s birth year and postal code\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCases: children born between 2001 and 2005 newly diagnosed with cancer between 1 January, 2004 to 1 January, 2006 at one of six collaborating hospitals;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eControls: children without cancer\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCases: 128/116\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eControls: 128/125\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eCases: 128/118\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eControls: 128/126\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eDoctor-diagnosed cancer at the mean age of 1.7 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eAge, socioeconomic status, mother\u0026rsquo;s and father\u0026rsquo;s educational level, history of the familial cancer syndrome and transplacental ionizing radiation\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width:100.0%;border:none;border-bottom: solid windowtext 1.0pt;background: #BFBFBF;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNeurodevelopmental disorders\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGolding 2017 [68]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e14,062/10,025\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e14,062/NR\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eAutism diagnosis identified from sources such as mother report and educational system by age 16 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eYear of birth of the maternal grandmother, the ages of the grandparents when the study mother was born, the parity of the maternal grandmother, and mother\u0026rsquo;s use of social housing, education, and locus of control\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\u003cspan style=\"font-size: 16px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eTable 1. Characteristics of\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eobservational epidemiologic s\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003etudies\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ei\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003envestigating\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003egrandmaternal\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003es\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003emoking during\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ep\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eregnancy and\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eh\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eealth\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eo\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eutcomes in the\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eg\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003erandchild\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;(continued)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003ctable style=\"width: 100%;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.12%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.18%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eCountry\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.14%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy design\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:24.86%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eParticipants\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.2%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eExposure assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:13.8%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eOutcome assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:22.7%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eConfounding factors adjusted\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:13.82%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eSampling method, source\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:11.04%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNo. recruited/\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eanalyzed\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGolding 2020 [70]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/6,576\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/5,393\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eIntelligence quotient assessed by trained psychologists at age 8 and 15 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eAge of grandparent when parent was born, and ethnic background, education level and social class of grandparent\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGustavson 2017 [75]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNorway\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women in 1999-2008 in Norway\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/82,944\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMother report at 18 gestational weeks\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eADHD diagnosis records from the Norwegian Patient Registry at age 5\u0026ndash;15 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal and paternal age, education, and ADHD symptoms, maternal (pre-pregnancy) and paternal BMI, maternal smoking and alcohol consumption during pregnancy and parity, child\u0026rsquo;s birth year, and geographical region\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePembrey 2014 [50]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women who smoked during pregnancy in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/1,163\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/918\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eIntelligence quotient assessed by trained psychologists at age 8 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChild\u0026rsquo;s gestational age, maternal age, parity, education, birth weight, alcohol use and housing tenure, and paternal smoking at the start of pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;font-family:\"Arial\",sans-serif;'\u003e\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eTable 1. Characteristics of\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eobservational epidemiologic s\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003etudies\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ei\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003envestigating\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003egrandmaternal\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003es\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003emoking during\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ep\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eregnancy and\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eh\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eealth\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eo\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eutcomes in the\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eg\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003erandchild\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;(continued)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003ctable style=\"width: 100%;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.12%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.18%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eCountry\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.14%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy design\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:24.86%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eParticipants\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.2%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eExposure assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:13.8%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eOutcome assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:22.7%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eConfounding factors adjusted\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:13.82%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eSampling method, source\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:11.04%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNo. recruited/\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eanalyzed\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width:100.0%;border:none;border-bottom: solid windowtext 1.0pt;background: #BFBFBF;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eDiseases of the visual system\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eWilliams 2019 [73]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e14,062/6,995\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e14,062/4,099\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eEarly-onset myopia assessed by study staff at age 7 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandparents\u0026rsquo; birth year, ethnicity, education, age at birth of parent and social group, grandmother\u0026rsquo;s parity, and maternal vision impairments\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width:100.0%;border:none;border-bottom: solid windowtext 1.0pt;background: #BFBFBF;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eDisorders of hearing\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eHall 2020 [71]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e14,062/6,657\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e14,062/4,075\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eIntolerance to loud sound determined through parental questionnaire at ages 6 and 13 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eYear of birth of each grandparent, age of grandfather at birth of the parent, and ethnic origins of both grandparents\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"8\" style=\"width:100.0%;border:none;border-bottom: solid windowtext 1.0pt;background: #BFBFBF;padding:0in 5.4pt 0in 5.4pt;height:.05in;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNutritional disorders\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eDing 2017 [49]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUSA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: all children\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from women who participated in Nurses\u0026rsquo; Health Study II (the Growing Up Today Study 2)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e10,907/6,583\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother report\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandchild-reported weight and height (used for determining overweight/obesity and BMI) at age 17\u0026ndash;22 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother\u0026rsquo;s gestational age, age at birth, level of education, consumption of alcohol, vegetable, fruit and meat, physical activity and weight gain during pregnancy, and mothers\u0026rsquo; pre-pregnancy BMI, smoking during pregnancy, social-economic status, and diet score and physical activity during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-size:16px;font-family:\"Arial\",sans-serif;'\u003e\u003cbr\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eTable 1. Characteristics of\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eobservational epidemiologic s\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003etudies\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ei\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003envestigating\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003egrandmaternal\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003es\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003emoking during\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003ep\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eregnancy and\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eh\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eealth\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eo\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eutcomes in the\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003eg\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003erandchild\u003c/span\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cspan style='font-family:\"Arial\",sans-serif;'\u003e\u0026nbsp;(continued)\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003ctable style=\"width: 100%;border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.12%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.18%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eCountry\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:10.14%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eStudy design\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:24.86%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eParticipants\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:9.2%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eExposure assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:13.8%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eOutcome assessment\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" style=\"width:22.7%;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:4.25pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eConfounding factors adjusted\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:13.82%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eSampling method, source\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:11.04%;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:4.2pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eNo. recruited/\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif;\"\u003eanalyzed\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eDing 2020 [54]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUSA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: all children\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from women who participated in Nurses\u0026rsquo; Health Study II (the Growing Up Today Study 1 and 2)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e27,805/14,001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother report\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandchild-reported weight and height (used for determining overweight/obesity and BMI) in adolescence and young adulthood\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother\u0026rsquo;s gestational age, age at birth, level of education, pre-pregnancy BMI, weight gain during pregnancy, diet quality score and physical activity\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eDougan 2016 [53]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUSA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: all children\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from women who participated in Nurses\u0026rsquo; Health Study II (the Growing Up Today Study 1)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eNR/3,433\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother report\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandchild-reported weight and height (used for determining overweight/obesity) at ages 12 and 17 years\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGrandmother\u0026rsquo;s pre-pregnancy BMI, grandmother\u0026rsquo;s age during pregnancy, grandmother\u0026rsquo;s education at time of pregnancy, and child\u0026rsquo;s age, television viewing, vigorous activity and Tanner stage of development\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10.12%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eGolding 2014 [69]\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.18%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eUK\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10.14%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eProspective cohort\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.82%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eSampling method: general population\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eChildren born from all pregnant women in southwest England with an expected delivery date between April 1, 1991 and December 31, 1992\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11.04%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eMaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e14,062/7,352\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003ePaternal line:\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003e14,062/5,994\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 9.2%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParent report during pregnancy\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 13.8%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eWeight, height, and BMI from 7 to 17 years of age, measured by study staff\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 22.7%;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;height: 0.05in;vertical-align: top;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin-top:1.0pt;margin-right:0in;margin-bottom:1.0pt;margin-left:0in;text-align:left;'\u003e\u003cspan style=\"font-size: 13px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eParity, maternal education, paternal smoking at the start of pregnancy, and housing tenure\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 11px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eAbbreviations: ADHD, attention deficit hyperactivity disorder; BMI, body mass index; ECRHS, the European Community Respiratory Health Survey; MBHMS, the Michigan Bone Health and Metabolism Study; NR, not reported.\u003c/span\u003e\u003c/p\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003csup\u003e\u003cspan style=\"font-size: 11px; font-family: Arial, sans-serif;\"\u003ea\u003c/span\u003e\u003c/sup\u003e\u003c/span\u003e\u003cspan style=\"font-size: 11px; font-family: Arial, sans-serif; color: rgb(0, 0, 0);\"\u003eBelgium, Denmark, Estonia, France, Germany, Iceland, Italy, Norway, Spain, Sweden, and United Kingdom.\u003c/span\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003eFigure 1. Flow diagram for study selection process\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003eFigure 2. Quality appraisal by outcome presented as percentages across all included studies\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eEffects of grandmaternal smoking during pregnancy\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIn maternal line, 23 unique outcomes were reported from 24 study reports [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e47\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026ndash;\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e50\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e52\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026ndash;\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e54\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e68\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026ndash;\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e84\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e]. We conducted meta-analyses for birth weight, body mass index (BMI) after birth, overweight/obesity, and asthma. In paternal line, 12 unique outcomes were reported from 12 reports [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e47\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e48\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e50\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e68\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u0026ndash;\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e74\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e78\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e84\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], and meta-analysis was conducted for asthma. Figure\u0026nbsp;3 summarizes the effects of maternal and paternal grandmaternal smoking on categorical outcomes in the grandchild. The effects on continuous outcomes are summarized in eFigure 2 in Additional file 2. Below we describe the main results for these outcomes. The effects of grandmaternal and maternal smoking in combination are described in eResults in Additional file 2. More detailed results are available in eTables 3 and 7 in Additional file 2.\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003eFigure 3. Grandmaternal smoking during pregnancy and categorical outcomes in the grandchild\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eA. Maternal grandmaternal smoking. B. Paternal grandmaternal smoking. The effect estimates are for grandmaternal smoking compared to non-smoking regardless of maternal smoking status during pregnancy, unless otherwise indicated. The results for asthma and overweight/obesity are from robust random-effects meta-analysis. Abbreviations: Cc, case-control study; CI, confidence interval; Co, cohort study; NA, not available.\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003csup\u003ea\u003c/sup\u003e Among grandchildren whose mothers did not smoke during pregnancy.\u003c/span\u003e\u003c/p\u003e\n \u003cdiv class=\"Section3\" id=\"Sec8\"\u003e\n \u003ch2\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eDiseases of the respiratory system\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIn maternal line, grandmaternal smoking was associated with a small increased risk of asthma (seven reports [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e47\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e48\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e52\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e74\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e77\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e78\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e82\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 148,527 grandchildren, RR 1.10, 95% CI 1.02 to 1.18; Fig.\u0026nbsp;4A). In paternal line, no evidence of association was found for asthma (four reports [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e47\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e48\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e74\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e78\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 41,069 grandchildren, RR 1.01, 95% CI 0.85 to 1.19; Fig.\u0026nbsp;4B).\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e\u003cstrong\u003eFigure 4. Grandmaternal smoking during pregnancy and asthma development in the grandchild\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eA. Maternal grandmaternal smoking. B. Paternal grandmaternal smoking. Abbreviations: CI, confidence interval; cigs, cigarettes; MGM+, maternal grandmaternal smoking during pregnancy; pres, prescriptions.\u003c/span\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec9\"\u003e\n \u003ch2\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eDisorders of newborn related to length of gestation or fetal growth\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIn maternal line, among grandchildren whose mothers did not smoke during pregnancy, grandmaternal smoking was associated with higher birth weight (four reports [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e49\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e72\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e76\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e80\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 19,478 grandchildren, MD (g) 40.04, 95% CI 22.60 to 57.49; eFigure 1 in Additional file 2); there was suggestive evidence that grandmaternal smoking was associated with a decreased risk of small birth weight for gestational age (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e81\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 14,558 grandchildren, RR 0.90, 95% CI 0.84 to 0.96; Fig.\u0026nbsp;3A), higher birth length (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e72\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 6,392 grandchildren, MD (cm) 0.19, 95% CI 0.02 to 0.35; eFigure 2A in Additional file 2) and higher BMI at birth (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e72\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 6,332 grandchildren, MD (g/m\u003csup\u003e2\u003c/sup\u003e) 1.60, 95% CI 0.60 to 2.60; eFigure 2A in Additional file 2). No evidence of association was found for preterm birth, low birth weight, small birth length for gestational age, small head circumference for gestational age and head circumference at birth (Fig.\u0026nbsp;3A and eFigure 2A in Additional file 2). In paternal line, there was no evidence of association between grandmaternal smoking and birth weight, birth length, or BMI or head circumference at birth (eFigure 2B in Additional file 2).\u003c/span\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec10\"\u003e\n \u003ch2\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNeoplasms\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIn maternal line, there was suggestive evidence that grandmaternal smoking was associated with increased risks of any cancer (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e84\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 241 grandchildren, RR 2.20, 95% CI 1.10 to 4.90; Fig.\u0026nbsp;3A) and acute lymphoblastic leukaemia (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e84\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 72 grandchildren, RR 3.00, 95% CI 1.10 to 8.80; Fig.\u0026nbsp;3A). No evidence of association was found for retinoblastoma (Fig.\u0026nbsp;3A). In paternal line, there was no evidence of association between grandmaternal smoking and cancer risk (Fig.\u0026nbsp;3B).\u003c/span\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec11\"\u003e\n \u003ch2\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNeurodevelopmental disorders\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIn maternal line, there was suggestive evidence that grandmaternal smoking was associated with increased risks of ADHD (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e75\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 82,944 grandchildren, RR 1.22, 95% CI 1.09 to 1.36; Fig.\u0026nbsp;3A) and autism (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e68\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 10,025 grandchildren, RR 1.41, 95% CI 1.01 to 1.97; Fig.\u0026nbsp;3A). No evidence of association was found for IQ scores (eFigure 2A in Additional file 2). In paternal line, there was suggestive evidence that grandmaternal smoking was associated with lower IQ scores (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e70\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 5,406 grandchildren, MD -2.67, 95% CI -4.00 to -1.34; eFigure 2B in Additional file 2).\u003c/span\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec12\"\u003e\n \u003ch2\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eDiseases of the visual system\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eThere was suggestive evidence that grandmaternal smoking was associated with a decreased risk of early-onset myopia in both maternal (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e73\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 6,995 grandchildren, RR 0.60, 95% CI 0.40 to 0.91; Fig.\u0026nbsp;3A) and paternal line (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e73\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 4,099 grandchildren, RR 0.47 95% CI 0.28 to 0.79; Fig.\u0026nbsp;3B).\u003c/span\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec13\"\u003e\n \u003ch2\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eDisorders of hearing\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIn paternal line, there was suggestive evidence that grandmaternal smoking was associated with a decreased risk of intolerance to loud sound (one report [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e71\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 4,075 grandchildren, RR 0.81, 95% CI 0.65 to 0.99; Fig.\u0026nbsp;3B). No evidence of association was found in maternal line (Fig.\u0026nbsp;3A).\u003c/span\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec14\"\u003e\n \u003ch2\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eNutritional disorders\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eIn maternal line, there was no evidence of association between grandmaternal smoking and overweight/obesity (three reports [\u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e49\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e53\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e, \u003c/span\u003e\u003cspan class=\"CitationRef\" style=\"color: rgb(0, 0, 0);\"\u003e54\u003c/span\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003e], 24,017 grandchildren, RR 1.06, 95% CI 0.83 to 1.35; Fig.\u0026nbsp;3A). In both maternal and paternal line, no evidence of association was found for weight, height, and BMI after birth (eFigure 2 in Additional file 2).\u003c/span\u003e\u003c/p\u003e\n \u003c/div\u003e\n \u003cdiv class=\"Section3\" id=\"Sec15\"\u003e\n \u003ch2\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eSubgroup analyses\u003c/span\u003e\u003c/h2\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eThe subgroup results by maternal smoking status during pregnancy are presented in eFigures 3 and 4 in Additional file 2. In maternal line, the point estimates among grandchildren whose mothers smoked tended to point in an opposite direction from those among grandchildren whose mothers did not smoke for autism, birth weight, birth length, and BMI and head circumference at birth. In paternal line, a similar tendency was found for birth weight, birth length, BMI at birth, and height after birth.\u003c/span\u003e\u003c/p\u003e\n \u003cp\u003e\u003cspan style=\"color: rgb(0, 0, 0);\"\u003eThe subgroup results by sex of the grandchild are presented in eTables 6 and 10 in Additional file 2. In maternal line, there was suggestive evidence that the effects of grandmaternal smoking were more pronounced in boys than in girls for birth weight, birth length, BMI at birth, autism and intolerance to loud sound. In paternal line, there was suggestive evidence that the effect on early-onset myopia was more pronounced in boys than in girls.\u003c/span\u003e\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eSummary of key findings\u003c/h2\u003e \u003cp\u003eIn maternal line, grandmaternal smoking during pregnancy was associated with an increased risk of asthma and higher birth weight in the grandchild. There was suggestive evidence that maternal grandmaternal smoking was associated with increased risks of acute lymphoblastic leukaemia, any cancer, autism, and ADHD, decreased risks of early-onset myopia and small birth weight for gestational age, and higher birth length and BMI at birth. In paternal line, no evidence of association was found between grandmaternal smoking and asthma. There was suggestive evidence that paternal grandmaternal smoking was associated with lower IQ scores and decreased risks of early-onset myopia and intolerance to loud sound. Subgroup analyses suggested that some of the effects were more pronounced in boys than in girls.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eIn epidemiologic studies, it is vital that confounders are identified and adjusted for in the analysis as this is fundamental to deliberations on causal inference [\u003cspan citationid=\"CR85\" class=\"CitationRef\"\u003e85\u003c/span\u003e]. However, identification of a sufficient set of confounders to adjust for can be particularly challenging in multigenerational studies [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e]. Together with the data availability issues, the difficulty in confounder selection probably led to the inconsistency that a wide range of variables were controlled for across the included studies. In addition, the sensitivity analysis for residual confounding suggested that the results were generally not robust to potential residual confounding. Second, controversy exists that some maternal variables (e.g., smoking during pregnancy, birth weight, asthma) may in fact be potential mediators of (part of) the association between grandmaternal smoking and (some) grandchild outcomes [\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e, \u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e]. That is, if the analytical goal is to estimate the overall causal effects of grandmaternal smoking, adjustment for these variables would be unwarranted; and if the analytical goal is to estimate the direct causal effects, adjustment for them would not reduce confounding, but rather introduce selection bias, when there are unmeasured common causes of the adjusted variables and the outcomes [\u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e]. For example, maternal smoking during pregnancy can arguably be a mediator on a causal pathway between grandmaternal smoking and some grandchild outcomes (e.g., birth weight, asthma) (eFigure 5 in Additional file 2) [\u003cspan citationid=\"CR80\" class=\"CitationRef\"\u003e80\u003c/span\u003e, \u003cspan citationid=\"CR87\" class=\"CitationRef\"\u003e87\u003c/span\u003e]. Studies often stratified on or adjusted for maternal smoking during pregnancy. The interesting observation is that the point estimates for grandchild birth anthropometric measures (e.g., birth weight, birth length, BMI at birth) tended to point in an opposite direction between non-smoking and smoking mothers, suggesting that maternal smoking might qualitatively modify the effects of grandmaternal smoking on these outcomes. A similar phenomenon was reported in the so-called \u0026ldquo;birth weight paradox\u0026rdquo; [\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e], where studies investigated the effects of maternal smoking during pregnancy on infant mortality stratified on a potential mediator (birth weight), and found that maternal smoking was associated with higher mortality among normal-birth-weight infants, but lower mortality among low-birth-weight infants. Third, the measurement of the exposure and the confounders can be another important challenge in multigenerational studies. With the difficulty in long-term tracking of participants across generations, studies often had to rely on parental report of grandmaternal exposure and maternal proxies for grandmaternal characteristics, which is likely subject to measurement bias [\u003cspan citationid=\"CR90\" class=\"CitationRef\"\u003e90\u003c/span\u003e]. Fourth, for most of the outcomes, only one study existed in which multiple subgroup results were often reported. Given the potential limitations in the studies and/or multiple comparisons [\u003cspan citationid=\"CR91\" class=\"CitationRef\"\u003e91\u003c/span\u003e], these results are most appropriately viewed as hypothesis generation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eEpigenetic inheritance\u003c/h2\u003e \u003cp\u003eIt has been hypothesized that germline epigenetic inheritance may underlie the intergenerational transmission of the effects of maternal smoking during pregnancy [\u003cspan citationid=\"CR92\" class=\"CitationRef\"\u003e92\u003c/span\u003e]. Rat models found that perinatal nicotine exposure in F0 generation led to DNAm changes and histone modifications in the germ cells of F1 generation that will form F2 generation [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Human epigenome-wide association studies reported that grandmaternal smoking during pregnancy was related to differential DNAm in the grandchild [\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e, \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. In mammals, efficient epigenetic reprogramming occurs in the germline and in the early embryo to remove most of the epigenetic marks acquired during development or imposed by the environment [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Nevertheless, these studies provided evidence that some of the perinatal smoking/nicotine-induced epigenetic marks in F1 germ cells may escape the reprogramming and be transmitted to F2 generation. Importantly, epigenetic regulation is increasingly recognized to mediate at least in part the effects of maternal smoking during pregnancy [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. On the other hand, experimental animal evidence exists on the intergenerational transmission of perinatal nicotine-induced asthma and neurodevelopmental disorders (e.g., ADHD, autism). Perinatal nicotine exposure in F0 rats induced an asthma-like phenotype in F2 offspring [\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Nicotine exposure prior to and throughout breeding in F0 mice resulted in neurodevelopmental disorder-like phenotypes in F2 offspring, along with DNA hypomethylation in striatum and frontal cortex [\u003cspan additionalcitationids=\"CR94\" citationid=\"CR93\" class=\"CitationRef\"\u003e93\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR95\" class=\"CitationRef\"\u003e95\u003c/span\u003e]. Taken together, the co-transmission of perinatal nicotine-induced epigenetic marks and some disease risks observed in rodent models as well as the potential role of epigenetic regulation in disease pathogenesis indicates that germline epigenetic inheritance may underlie the intergenerational effects.\u003c/p\u003e \u003cp\u003eFurthermore, perinatal nicotine exposure in F0 rats could even induce gonadal DNAm changes in F2 generation as well as an asthma-like phenotype in F3 generation [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e, \u003cspan citationid=\"CR96\" class=\"CitationRef\"\u003e96\u003c/span\u003e]. The potential transgenerational effects of maternal smoking during pregnancy have not been explored in epidemiologic studies. In mammals, it is generally thought that environmentally induced epigenetic changes are rarely transgenerationally inherited [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Future animal studies are warranted to replicate these findings and elucidate the plausibility of transgenerational inheritance of perinatal nicotine-induced epigenetic marks.\u003c/p\u003e \u003cp\u003eMaternal smoking during pregnancy is associated with lower birth weight in the child, partly mediated through epigenetic regulation [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22 CR23 CR24 CR25\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. However, we found that maternal grandmaternal smoking during pregnancy was associated with higher birth weight in the grandchild. To our knowledge, no animal models exist in this regard and the potential mechanisms are yet unknown. One possible conjecture is that under \u003cem\u003ein utero\u003c/em\u003e smoking exposure (F0), the fetal environment could modify the development of the fetus (F1) and/or its germ cells to prepare the subsequent generation (F2) for a future smoking environment [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR76\" class=\"CitationRef\"\u003e76\u003c/span\u003e]. Mechanistic studies are warranted to understand the potential mechanisms underlying the increased birth weight in the grandchild exposed to maternal grandmaternal smoking.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003eImplications\u003c/h2\u003e \u003cp\u003eThe degree to which the observed associations between grandmaternal smoking and grandchild outcomes reflect causal effects or are due to biases remains unclear. As discussed above, one possible explanation for the associations could be residual confounding or other biases in the design of existing studies. However, given the significant concern over the potential intergenerational transmission of the effects of maternal smoking during pregnancy, there is a need to raise public awareness that the adverse effects of smoking during pregnancy may not be limited to the exposed child, but be transmitted to the grandchild. In many countries, smoking during pregnancy remains an ongoing public health challenge [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. There is a need to stimulate further public health efforts to enhance smoking cessation programs for pregnant women.\u003c/p\u003e \u003cp\u003eFurther longitudinal multigenerational studies across different settings are warranted to strengthen the evidence. To handle confounding, investigators should explicitly specify the causal network linking the variables under investigation using their \u003cem\u003ea priori\u003c/em\u003e subject-matter knowledge, which can intuitively be presented in a causal diagram (e.g., directed acyclic graph (DAG)) [\u003cspan citationid=\"CR86\" class=\"CitationRef\"\u003e86\u003c/span\u003e, \u003cspan citationid=\"CR88\" class=\"CitationRef\"\u003e88\u003c/span\u003e]. The causal question that motivates the analytical approach should also be stated. It is worth noting that while identifying the direct causal effects of grandmaternal smoking may contribute to our understanding of the causal mechanisms for grandchild outcomes, from a public health perspective, the overall causal effects may be of greater interest [\u003cspan citationid=\"CR89\" class=\"CitationRef\"\u003e89\u003c/span\u003e]. Clarifying these aspects will help to provide a clearer framework for the interpretation and discussion of the results as well as for the evaluation of the proposed causal structures and analytical approaches. Further epigenetic research is needed to understand the potential role of germline epigenetic inheritance in the transmission of disease risks across generations.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eGrandmaternal smoking during pregnancy, particularly from the maternal than paternal line, is a risk factor for multiple health outcomes in the grandchild, indicating a transmission of effects across generations. Germline epigenetic inheritance might explain these intergenerational effects. There is a need for further public awareness on the intergenerational adverse effects of maternal smoking during pregnancy, which should inform smoking cessation programs for pregnant women.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eADHD, attention deficit hyperactivity disorder; BMI, body mass index; CI, confidence interval; DNAm, DNA methylation; EPHPP, the Effective Public Health Practice Project; IQ, intelligence quotient; MD, mean difference; PECOS, Population, Exposure, Comparator, Outcome, Study design; PROSPERO, the International Prospective Register of Systematic Reviews; RR, risk ratio; RVE, robust variance estimation.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analysed during the current study are available in the Open Science Framework repository, \u003ca href=\"https://osf.io/hav3t/?view_only=0c4f6c44aa994b0291cb7923bd5b633e\"\u003ehttps://osf.io/hav3t/?view_only=0c4f6c44aa994b0291cb7923bd5b633e\u003c/a\u003e.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHK reports personal fees and non-financial support from AstraZeneca, personal fees from Chiesi Pharma AB, personal fees and non-financial support from Boehringer-Ingelheim, personal fees from Novartis, personal fees from Mundipharma, personal fees and non-financial support from Orion Pharma, personal fees from SanofiGenzyme, personal fees from GlaxoSmithKline, outside the submitted work. All other authors have declared that no competing interests exist.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGQZ was supported by the VBG Group Herman Krefting Foundation on Asthma and Allergy, and Sahlgrenska Academy, University of Gothenburg, Sweden. BIN was supported by the VBG Group Herman Krefting Foundation on Asthma and Allergy, Knut and Alice Wallenberg Foundation, and the Wallenberg Centre for Molecular and Translational Medicine, University of Gothenburg, Sweden. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAS and BIN conceived the study. BIN performed the database searches. GQZ, YL, and BIN performed literature screening. GQZ, YL, and HHZ extracted data from the included studies and assessed study quality. GQZ performed the statistical analyses. GQZ and YL drafted the manuscript. All authors interpreted the results and critically revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe would like to thank [WAITING FOR WRITTEN PERMISSION] for providing additional data, [WAITING FOR WRITTEN PERMISSION] for statistical assistance, [WAITING FOR WRITTEN PERMISSION] for initial literature screening, and [WAITING FOR WRITTEN PERMISSION] for their contributions to developing the review protocol. They were not compensated for their contribution.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLange S, Probst C, Rehm J, Popova S. National, regional, and global prevalence of smoking during pregnancy in the general population: a systematic review and meta-analysis. Lancet Glob Health. 2018;6(7):e769\u0026ndash;76.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePereira PP, Da Mata FA, Figueiredo AC, de Andrade KR, Pereira MG. Maternal active smoking during pregnancy and low birth weight in the Americas: a systematic review and meta-analysis. Nicotine Tob Res. 2017;19(5):497\u0026ndash;505.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu B, Xu G, Sun Y, Qiu X, Ryckman KK, Yu Y, et al. Maternal cigarette smoking before and during pregnancy and the risk of preterm birth: a dose-response analysis of 25 million mother-infant pairs. PLoS Med. 2020;17(8):e1003158.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShah NR, Bracken MB. A systematic review and meta-analysis of prospective studies on the association between maternal cigarette smoking and preterm delivery. Am J Obstet Gynecol. 2000;182(2):465\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHackshaw A, Rodeck C, Boniface S. Maternal smoking in pregnancy and birth defects: a systematic review based on 173 687 malformed cases and 11.7 million controls. Hum Reprod Update. 2011;17(5):589\u0026ndash;604.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarufu TC, Ahankari A, Coleman T, Lewis S. Maternal smoking and the risk of still birth: systematic review and meta-analysis. BMC Public Health. 2015;15:239.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePineles BL, Hsu S, Park E, Samet JM. Systematic review and meta-analyses of perinatal death and maternal exposure to tobacco smoke during pregnancy. Am J Epidemiol. 2016;184(2):87\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAlm B, Milerad J, Wennergren G, Skjaerven R, Oyen N, Norvenius G, et al. A case-control study of smoking and sudden infant death syndrome in the Scandinavian countries, 1992 to 1995. The Nordic Epidemiological SIDS Study. Arch Dis Child. 1998;78(4):329\u0026ndash;34.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeuman \u0026Aring;, Hohmann C, Orsini N, Pershagen G, Eller E, Kjaer HF, et al. Maternal smoking in pregnancy and asthma in preschool children: a pooled analysis of eight birth cohorts. Am J Respir Crit Care Med. 2012;186(10):1037\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRayfield S, Plugge E. Systematic review and meta-analysis of the association between maternal smoking in pregnancy and childhood overweight and obesity. J Epidemiol Community Health. 2017;71(2):162\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBanderali G, Martelli A, Landi M, Moretti F, Betti F, Radaelli G, et al. Short and long term health effects of parental tobacco smoking during pregnancy and lactation: a descriptive review. J Transl Med. 2015;13:327.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCorr\u0026ecirc;a ML, Soares PSM, da Silva BGC, Wehrmeister F, Horta BL, Menezes AMB. Maternal smoking during pregnancy and intelligence quotient in offspring: a systematic review and meta-analysis. Neurotoxicology. 2021;85:99\u0026ndash;114.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGaysina D, Fergusson DM, Leve LD, Horwood J, Reiss D, Shaw DS, et al. Maternal smoking during pregnancy and offspring conduct problems: evidence from 3 independent genetically sensitive research designs. JAMA Psychiatry. 2013;70(9):956\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHe Y, Chen J, Zhu LH, Hua LL, Ke FF. Maternal smoking during pregnancy and ADHD: results from a systematic review and meta-analysis of prospective cohort studies. J Atten Disord. 2020;24(12):1637\u0026ndash;47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eU.S. Department of Health and Human Services. How Tobacco Smoke Causes Disease. The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health; 2010.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRogers JM. Tobacco and pregnancy. Reprod Toxicol. 2009;28(2):152\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKnopik VS, Marceau K, Bidwell LC, Rolan E. Prenatal substance exposure and offspring development: does DNA methylation play a role? Neurotoxicol Teratol. 2019;71:50\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNakamura A, Fran\u0026ccedil;ois O, Lepeule J. Epigenetic alterations of maternal tobacco smoking during pregnancy: a narrative review. Int J Environ Res Public Health. 2021;18(10):5083.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKungulovski G, Jeltsch A. Epigenome editing: state of the art, concepts, and perspectives. Trends Genet. 2016;32(2):101\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeard E, Martienssen RA. Transgenerational epigenetic inheritance: myths and mechanisms. Cell. 2014;157(1):95\u0026ndash;109.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eK\u0026uuml;pers LK, Xu X, Jankipersadsing SA, Vaez A, la Bastide-van Gemert S, Scholtens S, et al. DNA methylation mediates the effect of maternal smoking during pregnancy on birthweight of the offspring. Int J Epidemiol. 2015;44(4):1224\u0026ndash;1237.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMorales E, Vilahur N, Salas LA, Motta V, Fernandez MF, Murcia M, et al. Genome-wide DNA methylation study in human placenta identifies novel loci associated with maternal smoking during pregnancy. Int J Epidemiol. 2016;45(5):1644\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWitt SH, Frank J, Gilles M, Lang M, Treutlein J, Streit F, et al. Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation. BMC Genomics. 2018;19(1):290.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCardenas A, Lutz SM, Everson TM, Perron P, Bouchard L, Hivert MF. Mediation by placental DNA methylation of the association of prenatal maternal smoking and birth weight. Am J Epidemiol. 2019;188(11):1878\u0026ndash;86.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHannon E, Schendel D, Ladd-Acosta C, Grove J, Hansen CS, Hougaard DM, et al. Variable DNA methylation in neonates mediates the association between prenatal smoking and birth weight. Philos Trans R Soc Lond B Biol Sci. 2019;374(1770):20180120.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu R, Hong X, Zhang B, Huang W, Hou W, Wang G, et al. DNA methylation mediates the effect of maternal smoking on offspring birthweight: a birth cohort study of multi-ethnic US mother-newborn pairs. Clin Epigenetics. 2021;13(1):47.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilmot B, Fry R, Smeester L, Musser ED, Mill J, Nigg JT. Methylomic analysis of salivary DNA in childhood ADHD identifies altered DNA methylation in VIPR2. J Child Psychol Psychiatry. 2016;57(2):152\u0026ndash;60.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalton E, Pingault JB, Cecil CA, Gaunt TR, Relton CL, Mill J, et al. Epigenetic profiling of ADHD symptoms trajectories: a prospective, methylome-wide study. Mol Psychiatry. 2017;22(2):250\u0026ndash;6.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003evan Dongen J, Zilh\u0026atilde;o NR, Sugden K, Hannon EJ, Mill J, Caspi A, et al. Epigenome-wide association study of attention-deficit/hyperactivity disorder symptoms in adults. Biol Psychiatry. 2019;86(8):599\u0026ndash;607.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMooney MA, Ryabinin P, Wilmot B, Bhatt P, Mill J, Nigg JT. Large epigenome-wide association study of childhood ADHD identifies peripheral DNA methylation associated with disease and polygenic risk burden. Transl Psychiatry. 2020;10(1):8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeumann A, Walton E, Alemany S, Cecil C, Gonz\u0026aacute;lez JR, Jima DD, et al. Association between DNA methylation and ADHD symptoms from birth to school age: a prospective meta-analysis. Transl Psychiatry. 2020;10(1):398.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMeijer M, Klein M, Hannon E, van der Meer D, Hartman C, Oosterlaan J, et al. Genome-wide DNA methylation patterns in persistent attention-deficit/hyperactivity disorder and in association with impulsive and callous traits. Front Genet. 2020;11:16.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang IV, Pedersen BS, Liu A, O\u0026rsquo;Connor GT, Teach SJ, Kattan M, et al. DNA methylation and childhood asthma in the inner city. J Allergy Clin Immunol. 2015;136(1):69\u0026ndash;80.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eXu CJ, S\u0026ouml;derh\u0026auml;ll C, Bustamante M, Ba\u0026iuml;z N, Gruzieva O, Gehring U, et al. DNA methylation in childhood asthma: an epigenome-wide meta-analysis. Lancet Respir Med. 2018;6(5):379\u0026ndash;88.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eReese SE, Xu CJ, den Dekker HT, Lee MK, Sikdar S, Ruiz-Arenas C, et al. Epigenome-wide meta-analysis of DNA methylation and childhood asthma. J Allergy Clin Immunol. 2019;143(6):2062\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang Y, Forno E, Han YY, Xu Z, Hu D, Boutaoui N, et al. A genome-wide study of DNA methylation in white blood cells and asthma in Latino children and youth. Epigenetics. 2021;16(5):577\u0026ndash;85.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHoang TT, Sikdar S, Xu CJ, Lee MK, Cardwell J, Forno E, et al. Epigenome-wide association study of DNA methylation and adult asthma in the Agricultural Lung Health Study. Eur Respir J. 2020;56(3):2000217.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eM\u0026oslash;rkve Knudsen T, Rezwan FI, Jiang Y, Karmaus W, Svanes C, Holloway JW. Transgenerational and intergenerational epigenetic inheritance in allergic diseases. J Allergy Clin Immunol. 2018;142(3):765\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGruzieva O, Merid SK, Koppelman GH, Mel\u0026eacute;n E. An update on the epigenetics of asthma. Curr Opin Allergy Clin Immunol. 2021;21(2):175\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRehan VK, Liu J, Naeem E, Tian J, Sakurai R, Kwong K, et al. Perinatal nicotine exposure induces asthma in second generation offspring. BMC Med. 2012;10:129.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAltıntaş A, Liu J, Fabre O, Chuang TD, Wang Y, Sakurai R, et al. Perinatal exposure to nicotine alters spermatozoal DNA methylation near genes controlling nicotine action. FASEB J. 2021;35(7):e21702.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLiu J, Yu C, Doherty TM, Akbari O, Allard P, Rehan VK. Perinatal nicotine exposure-induced transgenerational asthma: effects of reexposure in F1 gestation. FASEB J. 2020;34(9):11444\u0026ndash;59.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWatkins SH, Iles-Caven Y, Pembrey M, Golding J, Suderman M. Grandmaternal smoking during pregnancy is associated with differential DNA methylation in their grandchildren. BioRxiv [Preprint]. 2021 bioRxiv 440892 [posted 2021 Apr 23; cited 2021 Dec 20]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.biorxiv.org/content/\u003c/span\u003e\u003cspan address=\"https://www.biorxiv.org/content/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1101/2021.04.22.440892v1\u003c/span\u003e\u003cspan address=\"10.1101/2021.04.22.440892v1\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e doi:10.1101/2021.04.22.440892.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo R, Zhang H, Mukherjee N, Karmaus W, Patil V, Arshad H, et al. Association of grandmaternal smoking during pregnancy with DNA methylation of grandchildren: the Isle of Wight study. Epigenomics. 2021;13(18):1473\u0026ndash;83.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHorsthemke B. A critical view on transgenerational epigenetic inheritance in humans. Nat Commun. 2018;9(1):2973.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePerez MF, Lehner B. Intergenerational and transgenerational epigenetic inheritance in animals. Nat Cell Biol. 2019;21(2):143\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBr\u0026aring;b\u0026auml;ck L, Lodge CJ, Lowe AJ, Dharmage SC, Olsson D, Forsberg B. Childhood asthma and smoking exposures before conception-a three-generational cohort study. Pediatr Allergy Immunol. 2018;29(4):361\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller LL, Henderson J, Northstone K, Pembrey M, Golding J. Do grandmaternal smoking patterns influence the etiology of childhood asthma? Chest. 2014;145(6):1213\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDing M, Yuan C, Gaskins AJ, Field AE, Missmer SA, Michels KB, et al. Smoking during pregnancy in relation to grandchild birth weight and BMI trajectories. PLoS ONE. 2017;12(7):e0179368.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePembrey M, Northstone K, Gregory S, Miller LL, Golding J. Is the growth of the child of a smoking mother influenced by the father's prenatal exposure to tobacco? A hypothesis generating longitudinal study. BMJ Open. 2014;4(7):e005030.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePage MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. PLoS Med. 2021;18(3):e1003583.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLodge CJ, Br\u0026aring;b\u0026auml;ck L, Lowe AJ, Dharmage SC, Olsson D, Forsberg B. Grandmaternal smoking increases asthma risk in grandchildren: a nationwide Swedish cohort. Clin Exp Allergy. 2018;48(2):167\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDougan MM, Field AE, Rich-Edwards JW, Hankinson SE, Glynn RJ, Willett WC, et al. Is grand-parental smoking associated with adolescent obesity? A three-generational study. Int J Obes. 2016;40(3):531\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDing M, Strohmaier S, Schernhammer E, Yuan C, Sun Q, Michels KB, et al. Grand-maternal lifestyle during pregnancy and body mass index in adolescence and young adulthood: an intergenerational cohort study. Sci Rep. 2020;10(1):14432.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWorld Health Organization. International Classification of Diseases, 11th Revision [cited 01 November 2021]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://icd.who.int/browse11/l-m/en\u003c/span\u003e\u003cspan address=\"https://icd.who.int/browse11/l-m/en\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eQuality Assessment Tool for Quantitative Studies [cited 13 July 2021]. Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.ephpp.ca/quality-assessment-tool-for-quantitative-studies/\u003c/span\u003e\u003cspan address=\"https://www.ephpp.ca/quality-assessment-tool-for-quantitative-studies/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang GQ, Chen JL, Luo Y, Mathur MB, Anagnostis P, Nurmatov U, et al. Menopausal hormone therapy and women's health: an umbrella review. PLoS Med. 2021;18(8):e1003731.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHedges LV, Tipton E, Johnson MC. Robust variance estimation in meta-regression with dependent effect size estimates. Res Synth Methods. 2010;1(1):39\u0026ndash;65.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTipton E. Small sample adjustments for robust variance estimation with meta-regression. Psychol Methods. 2015;20(3):375\u0026ndash;93.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiggins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539\u0026ndash;58.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR\u0026uuml;cker G, Schwarzer G, Carpenter JR, Schumacher M. Undue reliance on I\u003csup\u003e2\u003c/sup\u003e in assessing heterogeneity may mislead. BMC Med Res Methodol. 2008;8:79.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMathur MB, VanderWeele TJ. Sensitivity analysis for publication bias in meta-analyses. J R Stat Soc Ser C Appl Stat. 2020;69(5):1091\u0026ndash;119.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVanderWeele TJ, Ding P. Sensitivity analysis in observational research: introducing the E-value. Ann Intern Med. 2017;167(4):268\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMathur MB, VanderWeele TJ. Sensitivity analysis for unmeasured confounding in meta-analyses. J Am Stat Assoc. 2020;115(529):163\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMathur MB, Ding P, Riddell CA, VanderWeele TJ. Website and R package for computing E-values. Epidemiology. 2018;29(5):e45\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVanderWeele TJ. Optimal approximate conversions of odds ratios and hazard ratios to risk ratios. Biometrics. 2020;76(3):746\u0026ndash;52.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eR Core Team. (2021). R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.R-project.org/\u003c/span\u003e\u003cspan address=\"https://www.R-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGolding J, Ellis G, Gregory S, Birmingham K, Iles-Caven Y, Rai D, et al. Grand-maternal smoking in pregnancy and grandchild's autistic traits and diagnosed autism. Sci Rep. 2017;7:46179.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGolding J, Northstone K, Gregory S, Miller LL, Pembrey M. The anthropometry of children and adolescents may be influenced by the prenatal smoking habits of their grandmothers: a longitudinal cohort study. Am J Hum Biol. 2014;26(6):731\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGolding J, van den Berg G, Northstone K, Suderman M, Ellis G, Iles-Caven Y, et al. Grandchild's IQ is associated with grandparental environments prior to the birth of the parents. Wellcome Open Res. 2020;5:198.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHall A, Northstone K, Iles-Caven Y, Ellis G, Gregory S, Golding J, et al. Intolerance of loud sounds in childhood: is there an intergenerational association with grandmaternal smoking in pregnancy? PLoS ONE. 2020;15(2):e0229323.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMiller LL, Pembrey M, Davey Smith G, Northstone K, Golding J. Is the growth of the fetus of a non-smoking mother influenced by the smoking of either grandmother while pregnant? PLoS ONE. 2014;9(2):e86781.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliams C, Suderman M, Guggenheim JA, Ellis G, Gregory S, Iles-Caven Y, et al. Grandmothers' smoking in pregnancy is associated with a reduced prevalence of early-onset myopia. Sci Rep. 2019;9(1):15413.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAccordini S, Calciano L, Johannessen A, Portas L, Benediktsd\u0026oacute;ttir B, Bertelsen RJ, et al. A three-generation study on the association of tobacco smoking with asthma. Int J Epidemiol. 2018;47(4):1106\u0026ndash;17.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGustavson K, Ystrom E, Stoltenberg C, Susser E, Sur\u0026eacute;n P, Magnus P, et al. Smoking in pregnancy and child ADHD. Pediatrics. 2017;139(2):e20162509.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHypp\u0026ouml;nen E, Smith GD, Power C. Effects of grandmothers' smoking in pregnancy on birth weight: intergenerational cohort study. BMJ. 2003;327(7420):898.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMagnus MC, H\u0026aring;berg SE, Karlstad \u0026Oslash;, Nafstad P, London SJ, Nystad W. Grandmother's smoking when pregnant with the mother and asthma in the grandchild: the Norwegian Mother and Child Cohort Study. Thorax. 2015;70(3):237\u0026ndash;43.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMahon GM, Koppelman GH, Vonk JM. Grandmaternal smoking, asthma and lung function in the offspring: the Lifelines cohort study. Thorax. 2021;76(5):441\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRillamas-Sun E, Harlow SD, Randolph JF Jr. Grandmothers' smoking in pregnancy and grandchildren's birth weight: comparisons by grandmother birth cohort. Matern Child Health J. 2014;18(7):1691\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eShen Y, Zhang H, Jiang Y, Mzayek F, Arshad H, Karmaus W. Maternal birth weight and BMI mediate the transgenerational effect of grandmaternal BMI on grandchild's birth weight. Obesity. 2020;28(3):647\u0026ndash;54.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRumrich IK, H\u0026auml;nninen O, Viluksela M, V\u0026auml;h\u0026auml;kangas K. Effect of grandmaternal smoking on body size and proportions at birth. Int J Environ Res Public Health. 2021;18(9):4985.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLi YF, Langholz B, Salam MT, Gilliland FD. Maternal and grandmaternal smoking patterns are associated with early childhood asthma. Chest. 2005;127(4):1232\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAzary S, Ganguly A, Bunin GR, Lombardi C, Park AS, Ritz B, et al. Sporadic retinoblastoma and parental smoking and alcohol consumption before and after conception: a report from the Children's Oncology Group. PLoS ONE. 2016;11(3):e0151728.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eOrtega-Garc\u0026iacute;a JA, Martin M, L\u0026oacute;pez-Fern\u0026aacute;ndez MT, Fuster-Soler JL, Donat-Colomer J, L\u0026oacute;pez-Ibor B, et al. Transgenerational tobacco smoke exposure and childhood cancer: an observational study. J Paediatr Child Health. 2010;46(6):291\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHern\u0026aacute;n MA, Robins JM. Observational studies. In: Hern\u0026aacute;n MA, Robins JM, editors. Causal Inference: What If. Boca Raton: Chapman \u0026amp; Hall/CRC; 2020. pp.\u0026nbsp;25\u0026ndash;37.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHern\u0026aacute;n MA, Robins JM. Confounding. In: Hern\u0026aacute;n MA, Robins JM, editors. Causal Inference: What If. Boca Raton: Chapman \u0026amp; Hall/CRC; 2020. pp.\u0026nbsp;83\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArshad SH, Karmaus W, Zhang H, Holloway JW. Multigenerational cohorts in patients with asthma and allergy. J Allergy Clin Immunol. 2017;139(2):415\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHern\u0026aacute;n MA, Hern\u0026aacute;ndez-D\u0026iacute;az S, Werler MM, Mitchell AA. Causal knowledge as a prerequisite for confounding evaluation: an application to birth defects epidemiology. Am J Epidemiol. 2002;155(2):176\u0026ndash;84.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHern\u0026aacute;ndez-D\u0026iacute;az S, Schisterman EF, Hern\u0026aacute;n MA. The birth weight \"paradox\". uncovered? Am J Epidemiol. 2006;164(11):1115\u0026ndash;20.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHern\u0026aacute;n MA, Robins JM. Measurement bias. In: Hern\u0026aacute;n MA, Robins JM, editors. Causal Inference: What If. Boca Raton: Chapman \u0026amp; Hall/CRC; 2020. pp.\u0026nbsp;113\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun X, Briel M, Walter SD, Guyatt GH. Is a subgroup effect believable? Updating criteria to evaluate the credibility of subgroup analyses. BMJ. 2010;340:c117.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBreton CV, Landon R, Kahn LG, Enlow MB, Peterson AK, Bastain T, et al. Exploring the evidence for epigenetic regulation of environmental influences on child health across generations. Commun Biol. 2021;4(1):769.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuck JM, Sanders KN, Wageman CR, Knopik VS, Stitzel JA, O'Neill HC. Developmental nicotine exposure precipitates multigenerational maternal transmission of nicotine preference and ADHD-like behavioral, rhythmometric, neuropharmacological, and epigenetic anomalies in adolescent mice. Neuropharmacology. 2019;149:66\u0026ndash;82.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuck JM, O'Neill HC, Stitzel JA. Developmental nicotine exposure elicits multigenerational disequilibria in proBDNF proteolysis and glucocorticoid signaling in the frontal cortices, striata, and hippocampi of adolescent mice. Biochem Pharmacol. 2019;168:438\u0026ndash;51.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBuck JM, O'Neill HC, Stitzel JA. Developmental nicotine exposure engenders intergenerational downregulation and aberrant posttranslational modification of cardinal epigenetic factors in the frontal cortices, striata, and hippocampi of adolescent mice. Epigenetics Chromatin. 2020;13(1):13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRehan VK, Liu J, Sakurai R, Torday JS. Perinatal nicotine-induced transgenerational asthma. Am J Physiol Lung Cell Mol Physiol. 2013;305(7):L501\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acute lymphoblastic leukaemia, asthma, attention deficit hyperactivity disorder, autism, cancer, grandchild, grandmother, intelligence quotient, smoking during pregnancy, systematic review","lastPublishedDoi":"10.21203/rs.3.rs-1625650/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1625650/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eMaternal smoking during pregnancy is associated with a host of detrimental effects on the exposed child. However, emerging evidence suggests that the adverse effects of smoking during pregnancy may be transmitted across generations. We conducted a systematic review to comprehensively summarize evidence on the association between grandmaternal smoking during pregnancy and health outcomes in the grandchild.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe searched MEDLINE, EMBASE, and 10 other databases from inception to March 02, 2021, updated on October 18, 2021, to identify analytic epidemiologic studies (prospective or retrospective cohort and case-control design) investigating the association between grandmaternal smoking during pregnancy and multiple health outcomes in the grandchild in all countries and settings. Three investigators independently screened records, extracted data, and assessed study quality using the Effective Public Health Practice Project (EPHPP) tool. Random-effects robust variance estimation was used to combine effect estimates whenever possible, separately for maternal and paternal line.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTwenty-four reports from 15 unique studies with 23 health outcomes and 231,478 grandchildren were included. The overall study quality was moderate. In maternal line, grandmaternal smoking during pregnancy was associated with an increased risk of asthma (seven studies, 148,527 grandchildren, risk ratio (RR) 1.10, 95% CI 1.02 to 1.18) and higher birth weight (four studies, 19,478 grandchildren, mean difference (g) 40.04, 95% CI 22.60 to 57.49) in the grandchild. There was suggestive evidence that maternal grandmaternal smoking was associated with increased risks of acute lymphoblastic leukaemia, any cancer, autism, and attention deficit hyperactivity disorder, decreased risks of early-onset myopia and small birth weight for gestational age, and higher birth length and body mass index at birth. In paternal line, grandmaternal smoking during pregnancy was not associated with asthma (four studies, 41,069 grandchildren, RR 1.01, 95% CI 0.85 to 1.19), but there was suggestive evidence for lower intelligence quotient scores and decreased risks of early-onset myopia and intolerance to loud sound.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe effects of maternal smoking during pregnancy may not be limited to the exposed child, but be transmitted to the grandchild, possibly through germline epigenetic inheritance. Further public health efforts are warranted to strengthen smoking cessation programs for pregnant women.\u003c/p\u003e","manuscriptTitle":"Grandmaternal smoking during pregnancy and grandchild health: A systematic review and meta-analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-05-06 13:40:09","doi":"10.21203/rs.3.rs-1625650/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b9291dc4-1d66-45ab-81ff-1bef48fc544f","owner":[],"postedDate":"May 6th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-01-17T13:47:37+00:00","versionOfRecord":[],"versionCreatedAt":"2022-05-06 13:40:09","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-1625650","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1625650","identity":"rs-1625650","version":["v1"]},"buildId":"GqpaHPwrfC8PjnIFayRh5","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}