Early Environmental Risk Research Articles

High Maternal Body Mass Index in Early Pregnancy and Risks of Stillbirth and Infant Mortality-A Population-Based Sibling Study in Sweden.

In a population-based case-control study, we investigated whether familial confounding influenced the associations between maternal overweight/obesity and risks of stillbirth and infant mortality by including both population and sister controls. Using nationwide data from the Swedish Medical Birth Register (1992–2011), we included all primiparous women with singleton births who also had a sister with a first birth during that time period. We used logistic regression analyses to calculate odds ratios (and 95% confidence intervals) adjusted for maternal age, height, smoking habits, education, and time period (5-year groups) of child's birth. Body mass index (BMI) was calculated as weight (kg)/height (m)2. Compared with population controls with a normal BMI (18.5–24.9), stillbirth risk increased with increasing BMI (BMI 25–29.9: odds ratio (OR) = 1.51 (95% confidence interval (CI): 1.21, 1.89); BMI 30–34.9: OR = 1.77 (95% CI: 1.24, 2.50); BMI ≥35: OR = 3.16 (95% CI: 2.10, 4.76)). The sister case-control analyses revealed similar results. Offspring of obese women (BMI ≥30) had an increased risk of infant mortality when population controls were used (OR = 2.41, 95% CI: 1.83, 3.16), and an even higher risk was obtained when sister controls were used (OR = 4.04, 95% CI: 2.25, 7.25). We conclude that obesity in early pregnancy is associated with increased risks of stillbirth and infant mortality independently of genetic and early environmental risk factors shared within families.

Invited Commentary: Maternal Obesity and Impaired Fetal and Infant Survival-One More Piece Added to the Puzzle.

The association between maternal obesity and increased risks of stillbirth and infant mortality is well documented, but it has often been questioned whether the association is driven by obesity per se or by unmeasured factors such as insulin resistance or genes. In this issue of the Journal, Lindam et al. (Am J Epidemiol. 2016;184(2):98-105) present results from a sibling case-control study which strongly support that these tragic outcomes are independent of genetic and early environmental risk factors shared within families. By sampling sisters from the Swedish Medical Birth Register, Lindam et al. compared the body mass indices (weight (kg)/height (m)(2)) of women who had stillbirths and infant deaths with those of their sisters or of population controls. Significant excess risks of both outcomes were observed in obese women (body mass index ≥30), and associations were strongest when sister controls were used. Although this careful analysis adds to the existing evidence of a causal relationship between maternal obesity and impaired fetal and infant survival, a biological pathway has not yet been established. Additionally, we are in urgent need of effective tools to reduce obesity in childbearing women and to identify and treat high-risk pregnancies.

CHILDHOOD MALTREATMENT PREDICTS REDUCED INHIBITION-RELATED ACTIVITY IN THE ROSTRAL ANTERIOR CINGULATE IN PTSD, BUT NOT TRAUMA-EXPOSED CONTROLS.

A deficit in the ability to inhibit fear has been proposed as a biomarker of posttraumatic stress disorder (PTSD). Previous research indicates that individuals with PTSD show reduced inhibition-related activation in rostral anterior cingulate cortex (rACC). The goal of the current study was to investigate differential influences of an early environmental risk factor for PTSD-childhood maltreatment-on inhibition-related brain function in individuals with PTSD versus trauma-exposed controls. Individuals with PTSD (n = 37) and trauma-exposed controls (n = 53) were recruited from the primary care waiting rooms of an urban public hospital in Atlanta, GA. Participants completed an inhibition task during fMRI, and reported childhood and adult traumatic experiences. The groups were matched for adult and child trauma load. We observed an interaction between childhood maltreatment severity and PTSD status in the rACC (P < .05, corrected), such that maltreatment was negatively associated with inhibition-related rACC activation in the PTSD group, but did not influence rACC activation in the TC group. Rostral ACC activation was associated with inhibition-related task performance in the TC group but not the PTSD group, suggesting a possible contribution to stress resilience. Findings highlight individual differences in neural function following childhood trauma, and point to inhibition-related activation in rostral ACC as a risk factor for PTSD.

Severe Human Parechovirus Infections in Infants and the Role of Older Siblings.

Human parechovirus (HPeV) is a cause of severe morbidity among infants and young children. To evaluate the associations between early environmental risk factors and HPeV infections, we carried out a nationwide cohort study linking registry data on birth and sibship characteristics with a laboratory surveillance database, covering all HPeV infections detected in Denmark during 2009-2012 among children <5 years of age. Incidence rate ratios were calculated in log-linear Poisson regression analyses. Overall, 133 HPeV infections, 85 caused by human parechovirus type 3 (HPeV-3) and 48 by human parechovirus other than type 3 (non-HPeV-3), were detected among 132 children. Neither birth weight, mode of delivery, Apgar score, nor gestational age was associated with the risk of HPeV infections. Compared with firstborn children, secondborn children were at a 9-fold increased risk (incidence rate ratio = 8.68, 95% confidence interval: 3.85, 19.53) of contracting HPeV-3 infections, but at no increased risk of contracting non-HPeV-3 infections. However, the shorter the age gap to the nearest older sibling, the higher the risk of HPeV-3 as well as non-HPeV-3 infections, although the trend was strongest for HPeV-3 infections. Our study is the first to suggest that having a slightly older sibling increases the risk for severe neonatal HPeV infections. This new knowledge might lead to new preventive measures.

Interaction between COMT Val158Met polymorphism and childhood adversity affects reward processing in adulthood

BackgroundAccumulating evidence suggests that altered dopamine transmission may increase the risk of mental disorders such as ADHD, schizophrenia or depression, possibly mediated by reward system dysfunction. This study aimed to clarify the impact of the COMT Val158Met polymorphism in interaction with environmental variation (G×E) on neuronal activity during reward processing. Methods168 healthy young adults from a prospective study conducted over 25years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. DNA was genotyped for COMT, and childhood family adversity (CFA) up to age 11 was assessed by a standardized parent interview. ResultsAt reward delivery, a G×E revealed that fMRI activation for win vs. no-win trials in reward-related regions increased with the level of CFA in Met homozygotes as compared to Val/Met heterozygotes and Val homozygotes, who showed no significant effect. During the anticipation of monetary vs. verbal rewards, activation decreased with the level of CFA, which was also observed for EEG, in which the CNV declined with the level of CFA. ConclusionsThese results identify convergent genetic and environmental effects on reward processing in a prospective study. Moreover, G×E effects during reward delivery suggest that stress during childhood is associated with higher reward sensitivity and reduced efficiency in processing rewarding stimuli in genetically at-risk individuals. Together with previous evidence, these results begin to define a specific system mediating interacting effects of early environmental and genetic risk factors, which may be targeted by early intervention and prevention.

Associations Between Infant Negative Affect and Parent Anxiety Symptoms are Bidirectional: Evidence from Mothers and Fathers.

Little is known about child-based effects on parents’ anxiety symptoms early in life despite the possibility that child characteristics may contribute to the quality of the early environment and children’s own long-term risk for psychological disorder. We examined bidirectional effects between parent anxiety symptoms and infant negative affect using a prospective adoption design. Infant negative affect and adoptive parent anxiety symptoms were assessed at child ages 9, 18, and 27 months. Birth parent negative affect was assessed at child age 18 months. More anxiety symptoms in adoptive parents at child age 9 months predicted more negative affect in infants 9 months later. More infant negative affect at child age 9 months predicted more anxiety symptoms in adoptive parents 18 months later. Patterns of results did not differ for adoptive mothers and adoptive fathers. Birth parent negative affect was unrelated to infant or adoptive parent measures. Consistent with expectations, associations between infant negative affect and rearing parents’ anxiety symptoms appear to be bidirectional. In addition to traditional parent-to-child effects, our results suggest that infants’ characteristics may contribute to parent qualities that are known to impact childhood outcomes.

Maternal negative affect during infancy is linked to disrupted patterns of diurnal cortisol and alpha asymmetry across contexts during childhood

Maternal negative affect in the early environment is believed to sensitize long-term coping capacities in children. Yet, little work has identified physiological systems associated with coping responses, which may serve as mechanisms for links between early maternal negativity and child outcomes. Using a longitudinal twin sample (N=89), we found that high levels of maternal negative affect during infancy were associated with dysregulation of diurnal cortisol and electroencephalograph (EEG) asymmetry, two physiological systems that may support active approach-oriented coping when children are 7years old. Flattened slopes of diurnal cortisol were also associated with greater numbers of concurrent overanxious behaviors in children. A mediation analysis supported the role of dysregulated diurnal cortisol as a mediator of the link between maternal negative affect in the early environment and childhood risk for anxiety problems.

Early Life and Environmental Risk Factors Modify the Effect of Acculturation on Hispanic Children's Asthma.

Acculturation tends to erode Hispanic immigrants' initial health advantage. Using a more nuanced conceptualization of acculturation than previous studies, we explore the associations between acculturation and Hispanic children's asthma. Data came from an observational mail survey of caretakers of Hispanic schoolchildren in El Paso, Texas (N = 1,513). Results from generalized linear models (GzLMs) demonstrate that acculturation was a significant positive predictor of asthma. The addition of interaction terms revealed that prenatal smoking, low birth weight, breastfeeding, and pest exposure significantly modified the effect of acculturation on asthma. Results suggest that although higher levels of acculturation were detrimental overall, the effects were not equally damaging for all Hispanic children. Findings foster an understanding of how the effect of acculturation on Hispanic children's asthma is intensified or attenuated by distinct individual-level risk factors.

Identification of early environmental risk factors for irritable bowel syndrome and dyspepsia.

The role of childhood environment including exposure to infection via siblings and pets in irritable bowel syndrome (IBS) and dyspepsia is relatively unknown. We assessed proxy measures of microbial exposure in early childhood to assess if these are associated with IBS and functional dyspepsia in later life. Participants (n=767, response rate=53%) were a random population sample from Sydney, Australia who previously responded to a validated survey. IBS and functional dyspepsia were defined using Rome III criteria. Early environmental risk factors assessed included type of birth delivery, premature birth, breastfeeding, bedroom sharing, and pet exposure (the latter two then combined as early hygiene factors) up to 5years of age. Post infectious IBS (PI-IBS) was assessed by development of IBS following gastroenteritis. In this sample, in adult life 17% developed IBS (of which 20% had PI-IBS) and 12% functional dyspepsia. Development of IBS was associated with childhood factors-a shorter duration of breastfeeding (odds ratios [OR]=0.87, 95% CI: 0.78-0.97, p=0.01), sharing a bedroom (OR=1.89, 95% CI: 1.73-3.08, p=0.01), exposure to a herbivore pet (OR=1.65 (1.10, 2.48), p=0.02), and hygiene factors (OR=4.39; 95% CI: 1.89-10.21, p=0.001). The sole factor associated with functional dyspepsia was exposure to a herbivore pet (1.79; 95% CI: 1.19-2.87, p=0.02). Childhood environment factors, particularly bedroom sharing and pet exposure, combined with subsequent risk of microbial exposure are a risk factor for IBS in later life. These associations however need confirmation to rule out any risk of a type I error.

Promoter methylation of glucocorticoid receptor gene is associated with subclinical atherosclerosis: A monozygotic twin study.

Endothelial dysfunction assessed by brachial artery flow-mediated dilation (FMD) is a marker of early atherosclerosis. Glucocorticoid receptor gene (NR3C1) regulates many biological processes, including stress response, behavioral, cardiometabolic and immunologic functions. Genetic variants in NR3C1 have been associated with atherosclerosis and related risk factors. This study investigated the association of NR3C1 promoter methylation with FMD, independent of genetic and family-level environmental factors. We studied 84 middle-aged, male-male monozygotic twin pairs recruited from the Vietnam Era Twin Registry. Brachial artery FMD was measured by ultrasound. DNA methylation levels at 22 CpG residues in the NR3C1 exon 1F promoter region were quantified by bisulfite pyrosequencing in genomic DNA isolated from peripheral blood leukocytes. Co-twin control analyses were conducted to examine the association of methylation variation with FMD, adjusting for smoking, physical activity, body mass index, lipids, blood pressure, fasting glucose, and depressive symptoms. Multiple testing was corrected using the false discovery rate. Mean methylation level across the 22 studied CpG sites was 2.02%. Methylation alterations at 12 out of the 22 CpG residues were significantly associated with FMD. On average, a 1% increase in the intra-pair difference in mean DNA methylation was associated with 2.83% increase in the intra-pair difference in FMD (95% CI: 1.46-4.20; P < 0.0001) after adjusting for risk factors and multiple testing. Methylation variation in NR3C1 exon 1F promoter significantly influences subclinical atherosclerosis, independent of genetic, early family environmental and other risk factors.

The Effects of Vehicle Redesign on the Risk of Driver Death

Objectives: This study updates a 2006 report that estimated the historical effects of vehicle design changes on driver fatality rates in the United States, separate from the effects of environmental and driver behavior changes during the same period. In addition to extending the period covered by 8 years, this study estimated the effect of design changes by model year and vehicle type.Methods: Driver death rates for consecutive model years of vehicle models without design changes were used to estimate the vehicle aging effect and the death rates that would have been expected if the entire fleet had remained unchanged from the 1985 calendar year. These calendar year estimates are taken to be the combined effect of road environment and motorist behavioral changes, with the difference between them and the actual calendar year driver fatality rates reflecting the effect of changes in vehicle design and distribution of vehicle types. The effects of vehicle design changes by model year were estimated for cars, SUVs, and pickups by computing driver death rates for model years 1984–2009 during each of their first 3 full calendar years of exposure and comparing with the expected rates if there had been no design changes.Results: As reported in the 2006 study, had there been no changes in the vehicle fleet, driver death risk would have declined during calendar years 1985–1993 and then slowly increased from 1993 to 2004. The updated results indicate that the gradual increase would have continued through 2006, after which driver fatality rates again would have declined through 2012. Overall, it is estimated that there were 7,700 fewer driver deaths in 2012 than there would have been had vehicle designs not changed. Cars were the first vehicle type whose design safety generally exceeded that of the 1984 model year (starting in model year 1996), followed by SUVs (1998 models) and pickups (2002 models). By the 2009 model year, car driver fatality risk had declined 51% from its high in 1994, pickup driver fatality risk had declined 61% from its high in 1988, and SUV risk had declined 79% from its high in 1988. The risk of driver death in 2009 model passenger vehicles was 8% lower than that in 2008 models and about half that in 1984 models.Conclusions: Changes in vehicles, whether from government regulations and consumer testing that led to advanced safety designs or from other factors such as consumer demand for different sizes and types of vehicles, have been key contributors to the decline in U.S. motor vehicle occupant crash death rates since the mid-1990s. Since the early 1990s, environmental and behavioral risk factors have not shown similar improvement, until the recession of 2007, even though there are many empirically proven countermeasures that have been inadequately applied.

The effects of the interplay of genetics and early environmental risk on the course of internalizing symptoms from late childhood through adolescence.

Internalizing symptoms during adolescence and beyond is a major public health concern, particularly because severe symptoms can lead to the diagnosis of a number of serious psychiatric conditions. This study utilizes a unique sample with a complex statistical method in order to explore Gene × Environment interactions found in internalizing symptoms during adolescence. Data for this study were drawn from a longitudinal prevention intervention study (n = 798) of Baltimore city school children. Internalizing symptom data were collected using self-report and blood or saliva samples genotyped using Affymetrix 6.0 microarrays. A major depression polygenic score was created for each individual using information from the major depressive disorder Psychiatric Genetics Consortium and used as a predictor in a latent trait-state-occasion model. The major depressive disorder polygenic score was a significant predictor of the stable latent trait variable, which captures time-independent phenotypic variability. In addition, an early childhood stressor of death or divorce was a significant predictor of occasion-specific variables. A Gene × Environment interaction was not a significant predictor of the latent trait or occasion variables. These findings support the importance of genetics on the stable latent trait portion of internalizing symptoms across adolescence.

Brain adaptation and alternative developmental trajectories.

Resilience and adaptation in the face of early genetic or environmental risk has become a major interest in child psychiatry over recent years. However, we still remain far from an understanding of how developing human brains as a whole adapt to the diffuse and widespread atypical synaptic function that may be characteristic of some common developmental disorders. The first part of this paper discusses four types of whole-brain adaptation in the face of early risk: redundancy, reorganization, niche construction, and adjustment of developmental rate. The second part of the paper applies these adaptation processes specifically to autism. We speculate that key features of autism may be the end result of processes of early brain adaptation, rather than the direct consequences of ongoing neural pathology.

Effects of genetic and early environmental risk factors for depression on serotonin transporter expression and methylation profiles.

The serotonin transporter (SERT) gene-linked polymorphic region (5-HTTLPR) has been implicated in moderating the link between life stress and depression. However, respective molecular pathways of gene–environment (GxE) interaction are largely unknown. Sustained alterations in SERT gene expression profiles, possibly mediated by epigenetic modifications, are a frequent correlate of depression and may thus constitute a putative mediator of GxE interaction. Here, we aimed to investigate joint effects of 5-HTTLPR and self-reported environmental adversity throughout the lifespan (prenatal, early and recent stress/trauma) on in vivo SERT mRNA expression in peripheral blood cells. To further evaluate whether environmentally induced changes in SERT expression are mediated by epigenetic modifications, we analyzed 83 CpG sites within a 799-bp promoter-associated CpG island of the SERT gene using the highly sensitive method of bisulfite pyrosequencing. Participants were 133 healthy young adults. Our findings show that both the 5-HTTLPR S allele and maternal prenatal stress/child maltreatment are associated with reduced in vivo SERT mRNA expression in an additive manner. Remarkably, individuals carrying both the genetic and the environmental risk factors exhibited 32.8% (prenatal stress) and 56.3% (child maltreatment) lower SERT mRNA levels compared with those without any risk factor. Our data further indicated that changes in SERT mRNA levels were unlikely to be mediated by DNA methylation profiles within the SERT CpG island. It is thus conceivable that the persistent changes in SERT expression may in turn relate to altered serotonergic functioning and possibly convey differential disease vulnerability associated with 5-HTTLPR and early adversity.

Facteurs de risque précoces et trajectoires développementales du trouble déficit de l’attention/hyperactivité (TDAH)

Attention Deficit/Hyperactivity Disorder (ADHD) is associated with a set of early genetic and environmental risk factors. Genetic risk factors, of which existence is supported by genetically informed (i.e. Twin) and molecular studies, are yet partially identified. They do not constitute diagnostic markers or therapeutic targets for preventive interventions. Early environmental risk factors exist and could represent targets for early interventions. However, their causal nature is not determined yet. In addition, early environmental risk factors are distal factors compared with later risk factors, which makes difficult the understanding of their direct links with the ADHD phenotype. Developmental trajectories of ADHD are interesting to study in order to take into account the dimensional and developmental nature of ADHD. Investigating the link between early risk factors and developmental trajectories could allow a better understanding of their interactions along time. The experiment of preventive interventions of ADHD could lead to disentangle mechanisms and provide new tools to treat ADHD.

Environmental Risk Factors by Gender Associated With Attention-Deficit/Hyperactivity Disorder

Early environmental risk factors associated with attention-deficit/hyperactivity disorder (ADHD) have been increasingly suggested. Our study investigates the maternal, pregnancy, and newborn risk factors by gender for children prescribed stimulant medication for treatment of ADHD in Western Australia. This is a population-based, record linkage case-control study. The records of all non-Aboriginal children and adolescents born in Western Australia and aged <25 years who were diagnosed with ADHD and prescribed stimulant medication (cases = 12,991) were linked to the Midwives Notification System (MNS) to obtain maternal, pregnancy, and birth information. The control population of 30,071 children was randomly selected from the MNS. Mothers of children with ADHD were significantly more likely to be younger, be single, have smoked in pregnancy, have labor induced, and experience threatened preterm labor, preeclampsia, urinary tract infection in pregnancy, or early term delivery irrespective of the gender of the child, compared with the control group. In the fully adjusted model, a novel finding was of a possible protective effect of oxytocin augmentation in girls. Low birth weight, postterm pregnancy, small for gestational age infant, fetal distress, and low Apgar scores were not identified as risk factors. Smoking in pregnancy, maternal urinary tract infection, being induced, and experiencing threatened preterm labor increase the risk of ADHD, with little gender difference, although oxytocin augmentation of labor appears protective for girls. Early term deliveries marginally increased the risk of ADHD. Studies designed to disentangle possible mechanisms, confounders, or moderators of these risk factors are warranted.

Adolescent risk-taking as a function of prenatal cocaine exposure and biological sex

ObjectiveTo examine the effects of prenatal cocaine exposure and biological sex on adolescent risk-taking while controlling for early environmental risk. MethodsAdolescents (n=114, mean age=16) were grouped according to high and low risk-taking propensity as measured by the Balloon Analogue Risk Task (BART). Prenatal cocaine exposure was assessed at birth, while environmental risk was assessed at three points during early childhood. ResultsA binary regression analysis indicated that males were 3.5 times more likely than females to be high risk-takers. Biological sex and prenatal cocaine exposure interacted such that exposed males were most likely to be high risk-takers while exposed females were the least likely to be high risk-takers. This pattern held after controlling for prenatal alcohol exposure and early environmental risk. Early environmental risk did not predict adolescent risk-taking. ConclusionsThese findings complement and extend earlier research demonstrating that prenatal cocaine exposure interacts with biological sex in domains related to inhibitory control, emotion regulation, antisocial behavior, and health risk behaviors during preadolescence.

Mo2046 Identification of Early Environmental Risk Factors for Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD)

Mo2046 Identification of Early Environmental Risk Factors for Irritable Bowel Syndrome (IBS) and Functional Dyspepsia (FD)

2099 – Clinical risk factors for interpersonal violence in adulthood in suicide attempters

Introduction Early environmental risk factors have a role in the development of violent behaviour in adulthood. Aims The aim of the study was to assess the impact of childhood trauma, expressed violent behaviour as a child, co morbid personality disorder and substance abuse on self reported interpersonal violence as an adult in suicide attempters. Methods A total of 161 suicide attempters were diagnosed with SCID I and II and assessed with the Karolinska Interpersonal Violence Scale (KIVS) measuring exposure to violence and expressed violent behaviour in childhood (between 6-14 years of age) and during adult life (15 years or older). A standard linear regression analyses was conducted with the two predictive KIVS subscales exposure to violence as a child and expressed violent behaviour as a child, Axis 1 mood and anxiety disorder diagnosis, co morbid substance abuse diagnosis, co morbid personality disorder diagnosis, age and gender as predictors of expressed interpersonal violence as an adult. Results The regression model was significant with adjusted R square 0.22, F ratio 7.2, DF=7, p Conclusions It is important to take into account expressed violent behaviour in childhood in violence risk assessments.

Family history of suicide and exposure to interpersonal violence in childhood predict suicide in male suicide attempters

BackgroundFamily studies, including twin and adoption designs, have shown familial transmission of suicidal behaviors. Early environmental risk factors have an important role in the etiology of suicidal behavior. The aim of the present study was to assess the impact of family history of suicide and childhood trauma on suicide risk and on severity of suicide attempt in suicide attempters. MethodsA total of 181 suicide attempters were included. Family history of suicide was assessed with the Karolinska Suicide History Interview or through patient records. Childhood trauma was assessed with the Karolinska Interpersonal Violence Scale (KIVS) measuring exposure to violence and expressed violent behavior in childhood (between 6 and 14 years of age) and during adult life (15 years or older). Suicide intent was measured with the Freeman scale. ResultsMale suicide attempters with a positive family history of suicide made more serious and well planned suicide attempts and had a significantly higher suicide risk. In logistic regression, family history of suicide and exposure to interpersonal violence as a child were independent predictors of suicide in male suicide attempters. LimitationsThe information about family history of suicide and exposure to interpersonal violence as a child derives from the patients only. In the first part of the inclusion period the information was collected from patient records. ConclusionsThe results of this study imply that suicides among those at biological risk might be prevented with the early recognition of environmental risks.