Intergenerational transmission of tobacco smoking: The role of the child's behavioral difficulties. Data from the Danish National Birth cohort (DNBC).

AIMS: This study explores the role of offspring behavioral difficulties in the intergeneration transmission of tobacco smoking. METHODS: This longitudinal cohort study is based on children born in Denmark in 1996-2003 participating in the Danish National Birth Cohort (DNBC), followed-up until 18years of age. We included mother-child pairs with complete data regarding the exposure (4 trajectories of maternal daily smoking quantity during pregnancy: low, intermediate/stable, intermediate/decreasing and high), outcome (offspring daily smoking status at 18 years) and mediator (offspring symptoms of hyperactivity-inattention at 11 years), that is 24,588 mother-child pairs. RESULTS: In our study population, during pregnancy respectively 86.2%, 6.80%, 4.08% and 2.97% mothers belonged to the low, intermediate/stable, intermediate/decreasing and high smoking trajectory groups. After controlling for covariates using propensity scores, the direct effect of maternal smoking in pregnancy on offspring smoking in adolescence was statistically significant, especially when the mother belonged to the intermediate/stable smoking trajectory group (ORIPW = 2.09, 95% CI: 1.70 - 2.61) or to the high smoking trajectory group (ORIPW = 2.08, 95% CI: 1.52 - 3.11) compared to the low smoking trajectory group. None of the indirect effects of maternal smoking in pregnancy were statistically significant, and neither were the proportions mediated. CONCLUSION: Maternal pregnancy smoking seems to have an influence on offspring smoking in early adulthood, which does not appear to be mediated by offspring behavioral difficulties. Women should be strongly encouraged to quit smoking in pregnancy to reduce both short and long-term health risks among their offspring.

Epigenome-Wide Associations of Placental DNA Methylation and Behavioral and Emotional Difficulties in Children at 3 Years of Age.

The placenta is a key organ for fetal and brain development. Its epigenome can be regarded as a biochemical record of the prenatal environment and a potential mechanism of its association with the future health of the fetus. We investigated associations between placental DNA methylation levels and child behavioral and emotional difficulties, assessed at 3 years of age using the Strengths and Difficulties Questionnaire (SDQ) in 441 mother-child dyads from the EDEN cohort. Hypothesis-driven and exploratory analyses (on differentially methylated probes (EWAS) and regions (DMR)) were adjusted for confounders, technical factors, and cell composition estimates, corrected for multiple comparisons, and stratified by child sex. Hypothesis-driven analyses showed an association of cg26703534 (AHRR) with emotional symptoms, and exploratory analyses identified two probes, cg09126090 (intergenic region) and cg10305789 (PPP1R16B), as negatively associated with peer relationship problems, as well as 33 DMRs, mostly positively associated with at least one of the SDQ subscales. Among girls, most associations were seen with emotional difficulties, whereas in boys, DMRs were as much associated with emotional than behavioral difficulties. This study provides the first evidence of associations between placental DNA methylation and child behavioral and emotional difficulties. Our results suggest sex-specific associations and might provide new insights into the mechanisms of neurodevelopment.

Maternal Tobacco Smoking During Pregnancy and Children's Emotional and Behavioral Trajectories: The EDEN Mother-Child Birth Cohort Study.

INTRODUCTION: The nature of the relationship between maternal tobacco smoking during pregnancy and the occurrence of children's behavioral problems is still a matter of controversy. We tested this association using data collected among a sample of pregnant women and their offspring followed up from birth to early adolescence (age 12 years), accounting for multiple parent, child, and family characteristics. AIMS AND METHODS: Data come from 1424 mother-child pairs participating in the Étude des Déterminants pré et post-natals précoces du développement psychomoteur et de la santé de l'ENfant mother-child cohort in France. Using repeated measures (3, 5.5, 8, and 11.5 years) of the mother-reported Strengths and Difficulties Questionnaire, we estimated trajectories of children's emotional and behavioral difficulties. Two aspects of maternal smoking were studied: The timing (nonsmoker, smoking during the periconceptional period, or throughout pregnancy) and the level of use (cigarettes/day) during the first trimester of pregnancy. Robust Poisson regression models controlled for confounding factors including maternal mental health and socioeconomic characteristics using propensity scores with the overlap weighting technique. RESULTS: Contrary to bivariate analyses, in propensity score-controlled regression models, maternal smoking throughout pregnancy was no longer significantly associated with offspring emotional or behavioral difficulties. Maternal heavy smoking (≥10 cigarettes/day) remained significantly associated with intermediate levels of conduct problems (RR 1.25, 95% CI 1.19 to 1.31). CONCLUSIONS: The association between maternal smoking in pregnancy and offspring's emotional and behavioral difficulties appears to be largely explained by women's other characteristics. However, maternal heavy smoking appears to be related to offspring behavioral difficulties beyond the role of confounding characteristics. IMPLICATIONS: The relationship between maternal smoking during pregnancy (in two modalities: Timing and level of smoking) and behavioral difficulties in children is still a matter of debate. While the relationship between any maternal tobacco use and offspring behavioral difficulties appears to be largely explained by confounding factors, heavy maternal smoking in the first trimester of pregnancy seems to be associated with offspring behavioral difficulties beyond the socioeconomic and mental health characteristics transmitted across generations.

Epigenetic Alterations of Maternal Tobacco Smoking during Pregnancy: A Narrative Review.

In utero exposure to maternal tobacco smoking is the leading cause of birth complications in addition to being associated with later impairment in child's development. Epigenetic alterations, such as DNA methylation (DNAm), miRNAs expression, and histone modifications, belong to possible underlying mechanisms linking maternal tobacco smoking during pregnancy and adverse birth outcomes and later child's development. The aims of this review were to provide an update on (1) the main results of epidemiological studies on the impact of in utero exposure to maternal tobacco smoking on epigenetic mechanisms, and (2) the technical issues and methods used in such studies. In contrast with miRNA and histone modifications, DNAm has been the most extensively studied epigenetic mechanism with regard to in utero exposure to maternal tobacco smoking. Most studies relied on cord blood and children's blood, but placenta is increasingly recognized as a powerful tool, especially for markers of pregnancy exposures. Some recent studies suggest reversibility in DNAm in certain genomic regions as well as memory of smoking exposure in DNAm in other regions, upon smoking cessation before or during pregnancy. Furthermore, reversibility could be more pronounced in miRNA expression compared to DNAm. Increasing evidence based on longitudinal data shows that maternal smoking-associated DNAm changes persist during childhood. In this review, we also discuss some issues related to cell heterogeneity as well as downstream statistical analyses used to relate maternal tobacco smoking during pregnancy and epigenetics. The epigenetic effects of maternal smoking during pregnancy have been among the most widely investigated in the epigenetic epidemiology field. However, there are still huge gaps to fill in, including on the impact on miRNA expression and histone modifications to get a better view of the whole epigenetic machinery. The consistency of maternal tobacco smoking effects across epigenetic marks and across tissues will also provide crucial information for future studies. Advancement in bioinformatic and biostatistics approaches is key to develop a comprehensive analysis of these biological systems.

Maternal education and offspring birth weight for gestational age: the mediating effect of smoking during pregnancy.

BACKGROUND: Small for gestational age (SGA) birth weight, a risk factor for infant mortality and delayed child development, is associated with maternal educational attainment. Maternal tobacco smoking during pregnancy could contribute to this association. We aimed to quantify the contribution of maternal smoking during pregnancy to social inequalities in child birth weight for gestational age (GA). METHODS: Data come from the French nation-wide ELFE cohort study, which included 17 155 singletons. Birth weights for GA were calculated using z-scores. Associations between maternal educational attainment, tobacco smoking during pregnancy and child birth weight for GA were ascertained using mediation analysis. Mediation analyses were also stratified by maternal pre-pregnancy body mass index. RESULTS: Low maternal educational attainment was associated with an increased odd of tobacco smoking during pregnancy [adjusted OR (ORa) = 2.58 (95% CI 2.34-2.84)] as well as a decrease in child birth weight for GA [RRa = 0.94 (95% CI 0.91-0.98)]. Tobacco smoking during pregnancy was associated with a decrease in offspring birth weight for GA [RRa = 0.73 (95% CI 0.70-0.76)]. Mediation analysis suggests that 39% of the effect of low maternal educational attainment on offspring birth weight for GA was mediated by smoking during pregnancy. A more important direct effect of maternal educational attainment on child birth weight for GA was observed among underweight women [RRa = 0.82 (95% CI 0.72-0.93)]. CONCLUSIONS: The relationship between maternal educational attainment and child birth weight for GA is strongly mediated by smoking during pregnancy. Reducing maternal smoking could lessen the occurrence of infant SGA and decrease socioeconomic inequalities in birth weight for GA.

The role of prenatal social support in social inequalities with regard to maternal postpartum depression according to migrant status.

BACKGROUND: An advantaged socioeconomic position (SEP) and satisfying social support during pregnancy (SSP) have been found to be protective factors of maternal postpartum depression (PDD). An advantaged SEP is also associated with satisfying SSP, making SSP a potential mediator of social inequalities in PPD. SEP, SSP and PPD are associated with migrant status. The aim of this study was to quantify the mediating role of SSP in social inequalities in PPD regarding mother's migrant status. METHODS: A sub-sample of 15,000 mothers from the French nationally-representative ELFE cohort study was used for the present analyses. SEP was constructed as a latent variable measured with educational attainment, occupational grade, employment, financial difficulties and household income. SSP was characterized as perceived support from partner (good relation, satisfying support and paternal leave) and actual support from midwives (psychosocial risk factors assessment and antenatal education). Mediation analyses with multiple mediators, stratified by migrant status were conducted. RESULTS: Study population included 76% of non-migrant women, 12% of second and 12% of first generation migrant. SEP was positively associated with support from partner, regardless of migrant status. Satisfying partner support was associated with a 8 (non-migrant women) to 11% (first generation migrant women) reduction in PPD score. LIMITATIONS: History of depression was not reported. CONCLUSIONS: Partner support could reduce social inequalities in PPD. This work supports the need of interventions, longitudinal and qualitative studies including fathers and adapted to women at risk of PPD to better understand the role of SSP in social inequalities in PPD.

Informal and formal social support during pregnancy and joint maternal and paternal postnatal depression: Data from the French representative ELFE cohort study.

BACKGROUND: Insufficient social support has been intensively studied as a risk factor of postpartum depression (PPD) among mothers. However, to date, no study has examined the role of informal and formal dimensions of social support during pregnancy with regard to joint maternal and paternal depression after birth. AIM: Study associations between insufficient informal and formal support during pregnancy and joint parental PPD. METHODS: Using data from the nationally representative French ELFE (Etude Longitudinale Française depuis l'Enfance) cohort study (N = 12,350), we estimated associations between insufficient informal and formal support received by the mother during pregnancy and joint parental PPD in multi-imputed multivariate multinomial regression models. RESULTS: In 166 couples (1.3%), both parents were depressed. The likelihood of joint parental PPD was increased in case of insufficient informal support (insufficient partner support: odds ratio (OR) = 1.68 (95% confidence interval (CI): 1.57-1.80); frequent quarrels: OR = 1.38 (95% CI: 1.19-1.60)). We also observed associations between formal support during pregnancy and joint parental PPD (early prenatal psychosocial risk assessment: OR = 1.13 (95% CI: 1.05-1.22); antenatal education: OR = 1.13 (95% CI: 1.05-1.23)), which disappeared when analyses were restricted to women with no psychological difficulties during pregnancy. CONCLUSION: Insufficient informal social support during pregnancy appears to predict risk of joint PPD in mothers and fathers and should be identified early on to limit complications and the impact on children.

Which modifiable prenatal factors mediate the relation between socio-economic position and a child's weight and length at birth?

Although several studies have shown a positive association between socio-economic position and size at birth, not enough is known about the modifiable factors that may be involved. We aimed to investigate whether maternal prepregnancy body mass index (BMI), smoking, diet, and depression during pregnancy mediate the positive association between maternal education and birth size. Weight and length z-scores specific for gestational age and sex were calculated for 1,500 children from the EDEN mother-child cohort. A mediation analysis of the associations between maternal education and birth size was conducted with a counterfactual method, adjusted for recruitment centre, parity, maternal height, and age. In the comparison of children of mothers with low versus intermediate education levels, maternal smoking during pregnancy explained 52% of the total effect of education on birth weight. Similar findings were observed with birth length z-score (37%). The comparison of children of mothers with high versus intermediate education levels yielded a non-significant total effect, which masked opposite mediating effects by maternal BMI and smoking during pregnancy on both birth weight and length. Prepregnancy BMI and maternal smoking during pregnancy mediate the positive association between maternal education and birth weight and length z-scores. These mediators, however, act in opposite directions, thereby masking the extent to which healthy prenatal growth is socially differentiated.

Does liberalisation of cannabis policy influence levels of use in adolescents and young adults? A systematic review and meta-analysis.

OBJECTIVES: To examine the effect of cannabis policy liberalisation (decriminalisation and legalisation) levels of use in adolescents and young adults. DESIGN: Systematic review and meta-analysis. INCLUSION CRITERIA: Included studies were conducted among individuals younger than 25 years and quantitatively assessing consequences of cannabis policy change. We excluded articles: (A) exclusively based on participants older than 25 years; (B) only reporting changes in perceptions of cannabis use; (C) not including at least two measures of cannabis use; (D) not including quantitative data; and (E) reviews, letters, opinions and policy papers. PubMed, PsycINFO, Embase and Web of Science were searched through 1 March 2018. DATA EXTRACTION AND SYNTHESIS: Two independent readers reviewed the eligibility of titles and abstracts and read eligible articles, and four authors assessed the risk of bias (Quality Assessment Tool for Observational Cohort and Cross-Sectional Studies). Extracted data were meta-analysed. The protocol was registered with PROSPERO. RESULTS: 3438 records were identified via search terms and four via citation lists; 2312 were retained after removal of duplicates, 99 were assessed for eligibility and 41 were included in our systematic review. 13 articles examined cannabis decriminalisation, 20 examined legalisation for medical purposes and 8 examined legalisation for recreational purposes. Findings regarding the consequences of cannabis decriminalisation or legalisation for medical purposes were too heterogeneous to be meta-analysed. Our systematic review and meta-analysis suggest a small increase in cannabis use among adolescents and young adults following legalisation of cannabis for recreational purposes (standardised mean difference of 0.03, 95% CI -0.01 to -0.07). Nevertheless, studies characterised by a very low/low risk of bias showed no evidence of changes in cannabis use following policy modifications. CONCLUSIONS: Cannabis policy liberalisation does not appear to result in significant changes in youths' use, with the possible exception of legalisation for recreational purposes that requires monitoring. TRIAL REGISTRATION NUMBER: CRD42018083950.

Domain-specific physical activity and sedentary behavior during pregnancy and postpartum depression risk in the French EDEN and ELFE cohorts.

The potential beneficial effects of physical activity during pregnancy on postpartum depressive symptoms (PPD) remain inconclusive. Using data from two prospective French birth cohorts, we aimed to examine the relationship between domain-specific physical activity (including leisure-time sedentary behavior) in pregnancy and the occurrence of PPD. Participants of the ELFE cohort (n = 15,538) completed the Pregnancy Physical Activity Questionnaire (PPAQ), which assesses the following physical activity/sedentary behavior domains: household/caregiving, occupational, sports/exercise, transportation and leisure-time sedentary behavior during the third pregnancy trimester. In the EDEN cohort (n = 1745) women completed the Baecke Questionnaire (BQ) measuring occupational, sports/exercise, and leisure-time activity during the first trimester of pregnancy. Depressive symptoms in the first postpartum year were measured using the Edinburgh Postnatal Depression Scale in both cohorts. Associations of physical activity/sedentary behavior with PPD symptoms were determined by logistic regression analysis, with adjustment on potential confounding factors. In the adjusted models, higher levels of household/caregiving activities (OR = 1.10 (95% CI 1.01-1.19)) and leisure-time sedentary behavior (OR = 1.16 (95% CI 1.06-1.23)), in the third pregnancy trimester were associated with an increased odds of PPD. No significant associations were found for physical activity domains during the first pregnancy trimester. Higher levels of household and caregiving activities and leisure-time sedentary behavior in the last trimester of pregnancy appear to increase the likelihood of postpartum depression. Purpose and context should be taken into account when encouraging physical activity as a strategy to help prevent postpartum mental health problems from pregnancy onwards. Reducing sedentary behavior could be a complementary strategy.

Physical activity during pregnancy and postpartum depression: Systematic review and meta-analysis.

BACKGROUND: It is still largely unknown whether physical activity (PA) during pregnancy may be useful to avert subsequent postpartum depression (PPD). We conducted a systematic review and meta-analysis to determine the preventive effects of PA during pregnancy on PPD. METHODS: A systematic review of English and non-English articles was conducted using CINAHL, Cochrane Controlled Trials Register, PsycINFO, MEDLINE, SportDiscuss and Web of Science databases. Studies which tested the effect of any type of PA measured during pregnancy on depression or depressive symptoms in the first year postpartum were included. Relevant articles were extracted independently by 2 authors using predefined data fields, including study quality indicators. The protocol was registered on PROSPERO (CRD42018087086). RESULTS: Twenty one studies, fit our selection criteria. Among them, seventeen studies were included in the meta-analysis, representing 93 676 women. Robust Variance Estimation random-effects meta-analysis indicated a significant reduction in postpartum depression scores (Overall SMD = -0.22 [95% CI -0.42 to -0.01], p = 0.04; I2 = 86.4%) for women physically active during pregnancy relative to those who were not active. This association was reinforced in intervention studies (SMD = -0.58 [9% CI -1.09 to -0.08]). LIMITATIONS: Overall meta-analysis showed important heterogeneity in PA assessment, suggesting the existence of potential moderators such as intensity, frequency, trimester of pregnancy or type of physical activity practiced. CONCLUSIONS: PA during pregnancy appears to reduce the risk of PPD symptoms. High quality studies addressing the role of PA in the perinatal period and its impact on new mother's mental health remain necessary.

Subclinical psychosis in adult migrants and ethnic minorities: systematic review and meta-analysis.

BACKGROUND: It is well established that migration and ethnic minority status are risk factors for psychotic disorders. Recent studies have aimed to determine if they are also associated with subclinical psychosis (psychotic-like experiences and schizotypal traits). AIMS: We aimed to determine to what extent migrant and ethnic minority groups are associated with higher risk of subclinical psychosis. METHOD: We conducted a systematic review, using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement, and examined findings by ethnicity, migrant status, outcomes of subclinical psychosis and host country. A meta-analysis was carried out with robust variance estimation where possible, to handle statistically dependent effect size estimates. RESULTS: We included 28 studies (19 studies on psychotic-like experiences and 9 studies on schizotypal traits) and found that ethnicity, but not migrant status, was associated with current and lifetime psychotic-like experiences. In the narrative analysis, we observed the effect of psychosocial risk factors on this association: Black ethnicity groups showed consistent increased prevalence of current and lifetime psychotic-like experiences compared with the reference population across countries. CONCLUSIONS: More generalisable and standardised cohort studies of psychotic-like experiences and schizotypal traits in relation to migration/ethnicity are necessary to examine the effects of exposures and outcomes in different contexts, and to understand the underlying mechanisms of the association between subclinical psychosis and migrant and ethnic minority status. DECLARATION OF INTEREST: None.

Each pregnancy linearly changes immune gene expression in the blood of healthy women compared with breast cancer patients.

BACKGROUND: There is a large body of evidence demonstrating long-lasting protective effect of each full-term pregnancy (FTP) on the development of breast cancer (BC) later in life, a phenomenon that could be related to both hormonal and immunological changes during pregnancies. In this work, we studied the pregnancy-associated differences in peripheral blood gene expression profiles between healthy women and women diagnosed with BC in a prospective design. METHODS: Using an integrated system epidemiology approach, we modeled BC incidence as a function of parity in the Norwegian Women and Cancer (NOWAC) cohort (165,000 women) and then tested the resulting mathematical model using gene expression profiles in blood in a nested case-control study (460 invasive case-control pairs) of women from the NOWAC postgenome cohort. Lastly, we undertook a gene set enrichment analysis for immunological gene sets. RESULTS: A linear trend fitted the dataset precisely showing an 8% decrease in risk of BC for each FTP, independent of stratification on other risk factors and lasting for decades after a woman's last FTP. Women with six children demonstrated 48% reduction in the incidence of BC compared to nulliparous. When we looked at gene expression, we found that 756 genes showed linear trends in cancer-free controls (false discovery rate [FDR] 5%), but this was not the case for any of the genes in BC cases. Gene set enrichment analysis of immunologic gene sets (C7 collection in Molecular Signatures Database) revealed 215 significantly enriched human gene sets (FDR 5%). CONCLUSION: We found marked differences in gene expression and enrichment profiles of immunologic gene sets between BC cases and healthy controls, suggesting an important protective effect of the immune system on BC risk.

No overdiagnosis in the Norwegian Breast Cancer Screening Program estimated by combining record linkage and questionnaire information in the Norwegian Women and Cancer study.

BACKGROUND: The Norwegian Breast Cancer Screening Program (NBCSP) was implemented across the country in 2005 and has been criticised for potential 'overdiagnosis', i.e. a breast cancer diagnosis that otherwise would not have been detected or treated in a woman's lifetime. We aimed to estimate overdiagnosis in the NBCSP based on the Norwegian Women and Cancer (NOWAC) study using both questionnaire information and record linkage information from NBCSP. METHOD: For 124,978 women aged 49-79 years from the NOWAC study, information on screened women could be cross-validated from the NBCSP database. Based on information from the NOWAC questionnaire, unscreened women were further divided into those who had mammograms taken only outside the NBCSP and those who had never had taken a mammogram. Breast cancers diagnosed in 2005-2013 were identified through linkage to the Cancer Registry of Norway; in situ or DCIS 417; invasive 2845; combined 3262. Cumulative incidence rates (CIRs) for ages 49-79 years of breast cancer were compared using the log-rank test. RESULTS: After exclusion of women with a family history of breast cancer, screened women had a CIR of 9.7% for combined breast cancer, non-significantly lower compared with unscreened women. Screened women had a 1.1% increased CIR or 13.0% increased relative risk of breast cancer diagnosis (significant) compared with women who had never had a mammogram, but for invasive breast cancer alone the difference was reduced to -0.2% (95% CI: -9.1; 8.8). Invasive breast cancers were significantly smaller (<2.5 cm) in screened versus unscreened women. There was a borderline significant decrease in lymph node positive cancer among screened (p = 0.06). CONCLUSION: The findings of no significant overdiagnosis combined with smaller tumours and less lymph node metastases suggest that the prevailing view of overdiagnosis in the NBCSP should be challenged.

Reproductive factors and risk of mortality in the European Prospective Investigation into Cancer and Nutrition; a cohort study.

BACKGROUND: Reproductive events are associated with important physiologic changes, yet little is known about how reproductive factors influence long-term health in women. Our objective was to assess the relation of reproductive characteristics with all-cause and cause-specific mortality risk. METHODS: The analysis was performed within the European Investigation into Cancer and Nutrition prospective cohort study, which enrolled >500,000 women and men from 1992 to 2000, who were residing in a given town/geographic area in 10 European countries. The current analysis included 322,972 eligible women aged 25-70 years with 99 % complete follow-up for vital status. We assessed reproductive characteristics reported at the study baseline including parity, age at the first birth, breastfeeding, infertility, oral contraceptive use, age at menarche and menopause, total ovulatory years, and history of oophorectomy/hysterectomy. Hazard ratios (HRs) and 95 % confidence intervals (CIs) for mortality were determined using Cox proportional hazards regression models adjusted for menopausal status, body mass index, physical activity, education level, and smoking status/intensity and duration. RESULTS: During a mean follow-up of 12.9 years, 14,383 deaths occurred. The HR (95 % CI) for risk of all-cause mortality was lower in parous versus nulliparous women (0.80; 0.76-0.84), in women who had ever versus never breastfed (0.92; 0.87-0.97), in ever versus never users of oral contraceptives (among non-smokers; 0.90; 0.86-0.95), and in women reporting a later age at menarche (≥15 years versus <12; 0.90; 0.85-0.96; P for trend = 0.038). CONCLUSIONS: Childbirth, breastfeeding, oral contraceptive use, and a later age at menarche were associated with better health outcomes. These findings may contribute to the development of improved strategies to promote better long-term health in women.