Impact of prenatal maternal cytokine exposure on sex differences in brain circuitry regulating stress in offspring 45 years later.

Stress is associated with numerous chronic diseases, beginning in fetal development with in utero exposures (prenatal stress) impacting offspring's risk for disorders later in life. In previous studies, we demonstrated adverse maternal in utero immune activity on sex differences in offspring neurodevelopment at age seven and adult risk for major depression and psychoses. Here, we hypothesized that in utero exposure to maternal proinflammatory cytokines has sex-dependent effects on specific brain circuitry regulating stress and immune function in the offspring that are retained across the lifespan. Using a unique prenatal cohort, we tested this hypothesis in 80 adult offspring, equally divided by sex, followed from in utero development to midlife. Functional MRI results showed that exposure to proinflammatory cytokines in utero was significantly associated with sex differences in brain activity and connectivity during response to negative stressful stimuli 45 y later. Lower maternal TNF-α levels were significantly associated with higher hypothalamic activity in both sexes and higher functional connectivity between hypothalamus and anterior cingulate only in men. Higher prenatal levels of IL-6 were significantly associated with higher hippocampal activity in women alone. When examined in relation to the anti-inflammatory effects of IL-10, the ratio TNF-α:IL-10 was associated with sex-dependent effects on hippocampal activity and functional connectivity with the hypothalamus. Collectively, results suggested that adverse levels of maternal in utero proinflammatory cytokines and the balance of pro- to anti-inflammatory cytokines impact brain development of offspring in a sexually dimorphic manner that persists across the lifespan.

Prenatal maternal stress, child internalizing and externalizing symptoms, and the moderating role of parenting: findings from the Norwegian mother, father, and child cohort study.

BACKGROUND: Few studies have examined how parenting influences the associations between prenatal maternal stress and children's mental health. The objectives of this study were to examine the sex-specific associations between prenatal maternal stress and child internalizing and externalizing symptoms, and to assess the moderating effects of parenting behaviors on these associations. METHODS: This study is based on 15 963 mother-child dyads from the Norwegian Mother, Father, and Child Cohort Study (MoBa). A broad measure of prenatal maternal stress was constructed using 41 self-reported items measured during pregnancy. Three parenting behaviors (positive parenting, inconsistent discipline, and positive involvement) were assessed by maternal report at child age 5 years. Child symptoms of internalizing and externalizing disorders (depression, anxiety, attention-deficit hyperactivity disorder, conduct disorder, and oppositional-defiant disorder) were assessed by maternal report at age 8. Analyses were conducted using structural equation modeling techniques. RESULTS: Prenatal maternal stress was associated with child internalizing and externalizing symptoms at age 8; associations with externalizing symptoms differed by sex. Associations between prenatal maternal stress and child depression, and conduct disorder and oppositional-defiant disorder in males, became stronger as levels of inconsistent discipline increased. Associations between prenatal maternal stress and symptoms of attention-deficit hyperactivity disorder in females were attenuated as levels of parental involvement increased. CONCLUSIONS: This study confirms associations between prenatal maternal stress and children's mental health outcomes, and demonstrates that these associations may be modified by parenting behaviors. Parenting may represent an important intervention target for improving mental health outcomes in children exposed to prenatal stress.

Associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms throughout childhood.

BACKGROUND: Maternal immune activation is a potential mechanism underlying associations between maternal stress during pregnancy and offspring mental health problems. This study examined associations between prenatal maternal stress, maternal inflammation during pregnancy, and children's internalizing and externalizing symptoms from 3 to 10 years of age, and whether maternal inflammation mediated the associations between prenatal maternal stress and children's internalizing and externalizing symptoms. METHODS: This study comprised 4,902 mother-child dyads in the Generation R study. Prenatal maternal stress was assessed using self-reported data collected during pregnancy and analyzed as a latent variable consisting of four stress domains. Maternal inflammation during pregnancy was assessed using serum concentrations of C-reactive protein (CRP) measured at a median of 13.5 weeks' gestation. Child internalizing and externalizing symptoms were assessed using the Child Behavior Checklist (CBCL) by maternal report at ages 3 years, 5 years, and 10 years; paternal-reported CBCL data were also available at 3 years and 10 years. RESULTS: Prenatal maternal stress was associated with maternal-reported internalizing and externalizing symptoms of the child at 3, 5, and 10 years of age, and with paternal-reported internalizing and externalizing symptoms at 3 and 10 years. Prenatal maternal stress was associated with maternal CRP concentrations prior to, but not after, covariate adjustment. Maternal CRP concentrations during pregnancy were associated with paternal-reported internalizing symptoms of offspring at 10 years of age prior to, but not after, covariate adjustment. There was no evidence that CRP concentrations mediated the associations between prenatal maternal stress and children's internalizing or externalizing symptoms. CONCLUSIONS: Maternal stress during pregnancy is associated with higher levels of internalizing and externalizing symptoms in children, but this association is not because of differences in maternal immune activation linked to maternal stress. Replication of these findings in other cohorts is required; examination of other biomarkers or variation in immune activity during pregnancy would also benefit from further exploration.

Uncertainty in Developmental Origins of Health and Disease research: commentary on Nomura et al. (2023).

Nomura et al. (Journal of Child Psychology and Psychiatry, 2023) reported that children whose mothers were pregnant when Superstorm Sandy struck the Eastern Seaboard of the United States had elevated risk of psychopathology. Their study leverages data from a unique cohort of children established prior to Sandy that enabled researchers to investigate children's mental health depending on their prenatal exposure to the storm. Their findings add to mounting evidence that various types of prenatal stressors instigate stress responses that are transmitted to the developing fetus and impart enduring risk for neuropsychiatric disorders.

Children's cognitive performance and suicide risk through middle adulthood.

BACKGROUND: Longitudinal studies show that lower cognitive performance in adolescence and early adulthood is associated with higher risk of suicide death throughout adulthood. However, it is unclear whether this cognitive vulnerability originates earlier in childhood since studies conducted in children are scarce and have inconsistent results. METHODS: Vital status of 49,853 individuals born between 1959 and 1966 to participants in the Collaborative Perinatal Project cohort was determined by a probabilistic linkage to the National Death Index, covering all US deaths occurring from 1979 through 2016. Cox proportional hazard models were used to examine associations of general, verbal, and non-verbal intelligence at ages 4 and 7, and academic skills at age 7 with suicide death coded according to ICD-9/10 criteria, while accounting for sociodemographic and pregnancy factors previously associated with suicide in this sample. RESULTS: By the end of 2016, 288 cohort members had died by suicide. Cognitive performance at 7 years on tests with verbal components was associated with suicide risk (average vs. high verbal intelligence, HR = 1.97, 95% CI 1.05-3.71; low vs. high spelling skills, HR = 2.02, 95% CI 1.16-3.51; low vs. high reading skills, HR = 2.01, 95% CI 1.27-3.17). Associations were still evident, especially for verbal intelligence and reading skills, but hazard ratios were attenuated after adjusting for prenatal and sociodemographic factors at birth (verbal intelligence, HR = 1.97, 95% CI 1.03-3.78; spelling, HR = 1.61, 95% CI 0.90-2.88; reading, HR = 1.67, 95% CI 1.02-2.72). CONCLUSIONS: Childhood neurocognitive performance is associated with vulnerability to suicide mortality through middle-adulthood, suggesting that there might be a cognitive diathesis for suicide originating in early childhood. Future studies should examine how multiple domains of childhood cognitive performance contribute to vulnerability to suicide risk, including by increasing risk for social and environmental factors that are associated not only with suicide but also with many types of psychiatric disorders.

Positive maternal mental health attenuates the associations between prenatal stress and children's internalizing and externalizing symptoms.

Positive maternal mental health can improve perceptions of stressful situations and promote the use of adaptive coping strategies. However, few studies have examined how positive maternal mental health affects children's development. The aims of this study were to examine the associations between positive maternal mental health and children's internalizing and externalizing symptoms, and to ascertain whether positive maternal mental health moderated the associations between prenatal stress and children's internalizing and externalizing symptoms. This study is based on the Norwegian Mother, Father, and Child Cohort Study (MoBa), and comprised 36,584 mother-child dyads. Prenatal stress was assessed using 41 self-reported items measured during pregnancy. Positive maternal mental health (self-efficacy, self-esteem, and enjoyment) was assessed by maternal report during pregnancy and postpartum. Child internalizing and externalizing symptoms were assessed by maternal report at age 5. Structural equation modeling was used for analysis. Maternal self-efficacy, self-esteem, and enjoyment were negatively associated with internalizing and externalizing symptoms in males and females. The association between prenatal stress and internalizing symptoms in males was stronger at low than at high levels of maternal self-esteem and enjoyment, whereas for females, the association was stronger at low than at high levels of maternal self-esteem and self-efficacy. This study provides evidence of associations between positive maternal mental health and children's mental health, and suggests that higher positive maternal mental health may buffer against the impacts of prenatal stress. Positive maternal mental health may represent an important intervention target to improve maternal-child well-being and foster intergenerational resilience.

Advancing the Social Epidemiology Mission of the American Journal of Epidemiology.

Social epidemiology is concerned with how social forces influence population health. Rather than focusing on a single disease (as in cancer or cardiovascular epidemiology) or a single type of exposure (e.g., nutritional epidemiology), social epidemiology encompasses all the social and economic determinants of health, both historical and contemporary. These include features of social and physical environments, the network of relationships in a society, and the institutions, politics, policies, norms and cultures that shape all of these forces. This commentary presents the perspective of several editors at the Journal with expertise in social epidemiology. We articulate our thinking to encourage submissions to the Journal that: 1) expand knowledge of emerging and underresearched social determinants of population health; 2) advance new empirical evidence on the determinants of health inequities and solutions to advance health equity; 3) generate evidence to inform the translation of research on social determinants of health into public health impact; 4) contribute to innovation in methods to improve the rigor and relevance of social epidemiology; and 5) encourage critical self-reflection on the direction, challenges, successes, and failures of the field.

The developmental origins of suicide mortality: a systematic review of longitudinal studies.

Suicide prevention efforts generally target acute precipitants of suicide, though accumulating evidence suggests that vulnerability to suicide is partly established early in life before acute precipitants can be identified. The aim of this systematic review was to synthesize evidence on early life vulnerability to suicide beginning in the prenatal period and extending through age 12. We searched PubMed, Embase, PsycNet, Web of Science, Scopus, Social Services Abstracts, and Sociological Abstracts for prospective studies published through January 2021 that investigated early life risk factors for suicide mortality. The search yielded 13,237 studies; 54 of these studies met our inclusion criteria. Evidence consistently supported the link between sociodemographic (e.g., young maternal age at birth, low parental education, and higher birth order), obstetric (e.g., low birth weight), parental (e.g., exposure to parental death by external causes), and child developmental factors (e.g., exposure to emotional adversity) and higher risk of suicide death. Among studies that also examined suicide attempt, there was a similar profile of risk factors. We discuss a range of potential pathways implicated in these associations and suggest that additional research be conducted to better understand how early life factors could interact with acute precipitants and increase vulnerability to suicide.

Invited Commentary: The Disillusionment of Developmental Origins of Health and Disease (DOHaD) Epidemiology.

The developmental origins of health and disease (DOHaD) model promises a greater understanding of early development but has left unresolved the balance of risks and benefits to offspring of medication use during pregnancy. Masarwa et al. (Am J Epidemiol. 2018;187(8):1817-1827) conducted a meta-analysis of the association between in utero acetaminophen exposure and risks of attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). A challenge of meta-analyzing results from observational studies is that summary measures of risk do not correspond to well-defined interventions when the individual studies adjusted for different covariate sets, which was the case here. This challenge limits the usefulness of observational meta-analyses for inferences about etiology and treatment planning. With that limitation understood, Masarwa et al. reported a 20%-30% higher risk of ADHD and ASD following prenatal acetaminophen exposure. Surprisingly, most of the original studies did not report diagnoses of ADHD or ASD. As a result, their summary estimates of risk are not informative about children's likelihood of ADHD and ASD diagnoses. The long-term promise of DOHaD remains hopeful, but more effort is needed in the short-term to critically evaluate observational studies suggesting risks associated with medications used to treat conditions during pregnancy that might have adverse consequences for a developing fetus.

The Society for Epidemiologic Research and the Future of Diversity and Inclusion in Epidemiology.

"The mission of the Diversity and Inclusion Committee (D&I) in the Society for Epidemiologic Research is to foster the diversity of our membership and work towards the engagement of all members, from diverse backgrounds at all stages of their careers, in the Society's activities, with the intent of enhancing discovery in public health." As a foundational step in implementing our mission, the D&I Committee conducted a survey of SER membership. Here we report on the efforts we have undertaken to expand the diversity and inclusiveness of our Society and our aspirations for future efforts in support of D&I. Early on, we established the SERvisits program to conduct outreach to institutions and students that have historically been underrepresented at SER; we hope this program continues to grow in its reach and impact. We have also taken steps to increase the inclusiveness of SER activities, for example, by engaging members on issues of D&I through symposia and workshops at SER annual meetings and through social media. DeVilbiss et al. (Am J Epidemiol. 2020;189(10):998-1010) have demonstrated that there is substantial room for improvement with regards to diversity and inclusion within SER. We invite SER members to become involved and collaborate on this long-term goal.

Maternal Immune activity during pregnancy and socioeconomic disparities in children's self-regulation.

Maternal immune activity during pregnancy has been associated with risk for psychiatric disorders in offspring, but less is known about its implications for children's emotional and behavioral development. This study examined whether concentrations of five cytokines assayed from prenatal serum were associated with socioeconomic status (SES) and racial disparities in their offspring's self-regulation abilities. Participants included 1628 women in the Collaborative Perinatal Project (CPP). Seven behavioral items conceptually related to self-regulation were rated by CPP psychologists when children were 4 years old. Concentrations of interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α, and IL-10 were assessed. Covariates included child sex and mother's age, psychiatric disorders, and medical conditions during pregnancy. There were significant SES differences in child self-regulation, with higher SES children scoring higher on self-regulation (ß = 0.18, 95% CI [0.11, 0.25]), but no racial differences. The concentration of IL-8 in maternal serum was associated with higher child self-regulation, ß = 0.09, 95% CI [0.02, 0.16]. In mediation analyses, variation in maternal IL-8 contributed to the association between family SES and child self-regulation (ß = 0.02, 95% CI [0.003, 0.030]), explaining about one-tenth of the SES disparities. This study suggests pregnancy as an early sensitive period and maternal immune activity as an important context for child development.

Associations of types of green space across the life-course with blood pressure and body mass index.

Green space has been associated with better health and well-being. However, most studies have been cross-sectional with limited long-term exposure data. Further, research is limited in what type of green space is beneficial for health. We conducted a longitudinal study to assess sensitive periods (birth, childhood or adulthood) of exposure to different types of green space in association with adult blood pressure and body mass index (BMI). Using longitudinal data from the New England Family Study (1960-2000) and multilevel regression analysis, we examined associations between time-varying markers of residential exposure to green space, and adult BMI, systolic (SBP) and diastolic blood pressure (DBP) (N = 517). We created three exposure metrics: distance, average area, and green space count in the neighborhood throughout the life-course. In adjusted models, living one mile farther away from a green space at birth was associated with a 5.6 mmHg higher adult SBP (95%CI: 0.7, 10.5), and 3.5 mmHg higher DBP (95%CI: 0.3, 6.8). One more green space in the neighborhood at birth was also associated with lower DBP (-0.2 mmHg, 95%CI: -0.4, -0.02) in adulthood. Finally, average area of green space was not associated with SBP, DBP nor BMI. Analysis by type of green space suggested that parks may be more relevant than playgrounds, cemeteries or golf courses. Our study suggests that the perinatal period may be a critical time-period where living closer to green spaces may lower hypertension risk in adulthood, but not obesity.

Adolescent Mental Health Following Exposure to Positive and Harsh Parenting in Childhood.

OBJECTIVES: The purpose of the present study was to assess longitudinal associations between positive and harsh parenting in childhood and adolescent mental and behavioral difficulties. METHODS: Data were drawn from Canada's population-based National Longitudinal Survey of Children and Youth (data collected from 1994 to 2009, analyzed 2018). The sample included 9,882 adolescents aged 12/13 years old. Parents self-reported positive and harsh parenting when children were 6/7, 8/9, and 10/11 years old. Symptoms of depression/anxiety, hyperactivity, physical aggression, social aggression, and suicidal ideation were self-reported by adolescents at age 12/13. Linear regression was used to examine the associations between parenting behaviors at each age and adolescent psychiatric symptoms, adjusted for children's baseline symptoms. RESULTS: Harsh parenting at 10/11 was associated with elevated symptoms of early-adolescent physical aggression, social aggression, and suicidal ideation for boys only, and for all children at earlier ages. Beginning at age 8/9, harsh discipline was associated with elevated symptoms of depression/anxiety for boys only. Overall, positive parenting at age 6/7 was protective against depression/anxiety, physical aggression, and social aggression. Significant sex differences emerged beginning at age 8/9, with positive parenting associated with higher symptoms of depression/anxiety for boys only. Positive parenting at age 10/11 was associated with increased depression/anxiety, physical aggression, social aggression, and suicidal ideation among boys, but decreased symptoms of physical aggression, social aggression, and suicidal ideation among girls. CONCLUSIONS: Results suggest that the impact of positive and harsh parenting may depend on age and sex, with harsh parenting being more detrimental to boys as they approach adolescence.

Optimism and Social Support Predict Healthier Adult Behaviors Despite Socially Disadvantaged Childhoods.

BACKGROUND: Studies have shown adverse effects of a disadvantaged childhood on adult health-promoting behaviors and related outcomes. Optimism and social support have been linked to greater likelihood of engaging in healthy behavior, but it is unclear whether these positive psychosocial factors may buffer harmful effects of early adversity. This study aims to determine if optimism and social support in adulthood can modify effects of childhood disadvantage on health behavior-related outcomes. METHODS: Longitudinal data were analyzed from a subset of participants in a US birth cohort established in 1959-1966 (ns of 681-840, per outcome). An index of childhood social disadvantage was derived from adverse socioeconomic and family stability factors reported by mothers at child's birth and age 7 years. Health behavior-related outcomes were self-reported when participants were of mean age 47 years. Multivariable adjusted robust Poisson regressions were performed. RESULTS: Regardless of level of childhood social disadvantage, we found higher levels of optimism and social support were both associated with higher probabilities of being a non-smoker (relative risk [RR]optimism = 1.17, 95% confidence interval [CI] = 1.09-1.26; RRsocial support = 1.24, 95%CI = 1.11-1.39), having a healthy diet (RRoptimism = 1.25, 95%CI = 1.10-1.43; RRsocial support = 1.27, 95%CI = 1.04-1.56), and a healthy body mass index (RRoptimism = 1.18, 95%CI = 1.00-1.40; RRsocial support = 1.29, 95%CI = 1.00-1.66). Interactions link higher optimism or social support with lower risk of smoking among those with moderate childhood disadvantage. CONCLUSIONS: Overall, these findings are consistent with the possibility that positive psychosocial resources contribute to maintaining a healthy lifestyle in mid-adulthood and may buffer effects of childhood social disadvantage.

Socioeconomic disadvantage, gestational immune activity, and neurodevelopment in early childhood.

Children raised in economically disadvantaged households face increased risks of poor health in adulthood, suggesting that inequalities in health have early origins. From the child's perspective, exposure to economic hardship may begin as early as conception, potentially via maternal neuroendocrine-immune responses to prenatal stressors, which adversely impact neurodevelopment. Here we investigate whether socioeconomic disadvantage is associated with gestational immune activity and whether such activity is associated with abnormalities among offspring during infancy. We analyzed concentrations of five immune markers (IL-1ß, IL-6, IL-8, IL-10, and TNF-α) in maternal serum from 1,494 participants in the New England Family Study in relation to the level of maternal socioeconomic disadvantage and their involvement in offspring neurologic abnormalities at 4 mo and 1 y of age. Median concentrations of IL-8 were lower in the most disadvantaged pregnancies [-1.53 log(pg/mL); 95% CI: -1.81, -1.25]. Offspring of these pregnancies had significantly higher risk of neurologic abnormalities at 4 mo [odds ratio (OR) = 4.61; CI = 2.84, 7.48] and 1 y (OR = 2.05; CI = 1.08, 3.90). This higher risk was accounted for in part by fetal exposure to lower maternal IL-8, which also predicted higher risks of neurologic abnormalities at 4 mo (OR = 7.67; CI = 4.05, 14.49) and 1 y (OR = 2.92; CI = 1.46, 5.87). Findings support the role of maternal immune activity in fetal neurodevelopment, exacerbated in part by socioeconomic disadvantage. This finding reveals a potential pathophysiologic pathway involved in the intergenerational transmission of socioeconomic inequalities in health.

Peer victimisation and depression among gender conforming and non-conforming Thai adolescents.

Like most low- and middle-income countries, Thailand is facing an increasing burden of depressive disorders among adolescents, but research and services for them are largely neglected. This study explored the association between types of peer victimisation, gender non-conformity, health risk behaviours, and depressive symptoms among Thai students aged 13-18 years. Overall, prevalence of depressive symptoms was 14.7% (95% CI: 12.6-15.6), 12.2% (95% CI: 9.5-13.9) among male students and 16.5% (95% CI: 13.8-18.0) among female students. Among both sexes, social and sexual victimisation in the past month were strongly associated with depressive symptoms in the past week. Gender non-conforming female adolescents, as well as male and female adolescents who had experienced sexual and social victimisation, had a high burden of depressive symptoms. Mental health professionals and educators working with young people in Thailand should consider assessment for clinically significant depressive disorders.

Length of Fellowship Training in Population Health Research and Long-term Bibliometric Outcomes.

BACKGROUND: The length of research fellowships, the number of doctorates pursuing them, and the academic job market have changed dramatically in recent years. However, there is limited investigation on attributes of fellowships most relevant to future scientific achievement. We analyzed the association of a modifiable aspect of research training, fellowship length, with future achievement and differences across research discipline in the Division of Intramural Population Health Research (DIPHR), Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. METHODS: Demographics of 88 DIPHR trainees from 1998 to 2016 were collected from publicly available annual reports. Research performance metrics, including total publication count and H index through 2016, were collected via Scopus. We used linear regression models for associations between fellowship length, including both total exposure to research training and duration of postdoctoral training alone, and research performance adjusted for start year, publications at entry, branch (e.g., Biostatistics and Bioinformatics, Epidemiology, and Health Behavior), and mentor seniority. RESULTS: Each additional year of research training in DIPHR was associated with a 15% increase in H index (95% confidence interval [CI] = 3.0, 28.4) and 21% more lifetime publications (95% CI = 3.0, 41.9). Results were similar, although attenuated, when evaluating postdoctoral training alone. Differences by discipline were observed, with the strongest positive associations in the Biostatistics and Bioinformatics and Epidemiology Branches. CONCLUSIONS: Longer training at DIPHR was associated with improved measures of research performance, though this relationship varied by discipline. Additional research is needed to tailor training programs to optimize success of trainees.

Life Course Approaches to the Causes of Health Disparities.

Reducing health disparities requires an understanding of the mechanisms that generate disparities. Life course approaches to health disparities leverage theories that explain how socially patterned physical, environmental, and socioeconomic exposures at different stages of human development shape health within and across generations and can therefore offer substantial insight into the etiology of health disparities. Life course approaches are informed by developmental and structural perspectives. Developmental perspectives emphasize how socially patterned exposures to risk factors during sensitive life stages shift health trajectories, whereas structural perspectives emphasize how social identity and position within socially patterned environments disproportionately allocate risk factors and resources, resulting in altered health trajectories. We conclude that the science of health disparities will be advanced by integrating life course approaches into etiologic and intervention research on health disparities. The following 4 strategies are offered to guide in this process: (1) advance the understanding of multiple exposures and their interactions, (2) integrate life course approaches into the understanding of biological mechanisms, (3) explore transgenerational transmission of health disparities, and (4) integrate life course approaches into health disparities interventions.

A Bayesian regularized mediation analysis with multiple exposures.

Mediation analysis assesses the effect of study exposures on an outcome both through and around specific mediators. While mediation analysis involving multiple mediators has been addressed in recent literature, the case of multiple exposures has received little attention. With the presence of multiple exposures, we consider regularizations that allow simultaneous effect selection and estimation while stabilizing model fit and accounting for model selection uncertainty. In the framework of linear structural-equation models, we analytically show that a two-stage approach regularizing regression coefficients does not guarantee a unimodal posterior distribution and that a product-of-coefficient approach regularizing direct and indirect effects tends to penalize excessively. We propose a regularized difference-of-coefficient approach that bypasses these limitations. Using the connection between regularizations and Bayesian hierarchical models with Laplace prior, we develop an efficient Markov chain Monte Carlo algorithm for posterior estimation and inference. Through simulations, we show that the proposed approach has better empirical performances compared to some alternatives. The methodology is illustrated using data from two epidemiological studies in human reproduction.

Maternal smoking during pregnancy and offspring overweight: is there a dose-response relationship? An individual patient data meta-analysis.

BACKGROUND/OBJECTIVES: A number of meta-analyses suggest an association between any maternal smoking in pregnancy and offspring overweight obesity. Whether there is a dose-response relationship across number of cigarettes and whether this differs by sex remains unclear. SUBJECT/METHODS: Studies reporting number of cigarettes smoked during pregnancy and offspring BMI published up to May 2015 were searched. An individual patient data meta-analysis of association between the number of cigarettes smoked during pregnancy and offspring overweight (defined according to the International Obesity Task Force reference) was computed using a generalized additive mixed model with non-linear effects and adjustment for confounders (maternal weight status, breastfeeding, and maternal education) and stratification for sex. RESULTS: Of 26 identified studies, 16 authors provided data on a total of 238,340 mother-child-pairs. A linear positive association was observed between the number of cigarettes smoked and offspring overweight for up to 15 cigarettes per day with an OR increase per cigarette of 1.03, 95% CI = [1.02-1.03]. The OR flattened with higher cigarette use. Associations were similar in males and females. Sensitivity analyses supported these results. CONCLUSIONS: A linear dose-response relationship of maternal smoking was observed in the range of 1-15 cigarettes per day equally in boys and girls with no further risk increase for doses above 15 cigarettes.