Hélène Gaudreau

The Maternal Adversity, Vulnerability and Neurodevelopment Project: Theory and Methodology

Objective: To describe the theory and methodology of the multi-wave, prospective Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) study. The goal of MAVAN is to examine the pre- and postnatal influences, and their interaction, in determining individual differences in mental health. Method: MAVAN is a community-based, birth cohort study of pregnant Canadian mothers and their offspring. Dyads are assessed longitudinally, with multiple assessments of both mother and child in home and laboratory across the childs development. Study measures, including assessments of cognitive and emotional function, are described. The study uses a candidate gene approach to examine gene–environment interdependence in specific developmental outcomes. Finally, the study includes measures of both brain-based phenotypes and metabolism to explore comorbidities associated with child obesity. One of the unique features of the MAVAN protocol is the extensive measures of the mother–child interaction. The relation between these measures will be discussed. Results: Evidence from the MAVAN project shows interesting results about maternal care, families, and child outcomes. In our review, preliminary analyses showing the correlations between measures of maternal care are reported. As predicted, early evidence suggests that maternal care measures are positively correlated, over time. Conclusions: This review provides evidence for the feasibility and value of laboratory-based measures embedded within a longitudinal birth cohort study. Though retention of the samples has been a challenge of MAVAN, they are within a comparable range to other studies of this nature. Indeed, the trade-off of somewhat greater participant burden has allowed for a rich database. The results yielded from the MAVAN project will not only describe typical development but also possible targets for intervention. Understanding certain endophenotypes will shed light on the pathogenesis of various mental and physical disorders, as well as their interrelation.

Genetic Differential Susceptibility to Socioeconomic Status and Childhood Obesogenic Behavior: Why Targeted Prevention May Be the Best Societal Investment

IMPORTANCE Genes may work by modulating the way individuals respond to environmental variation, and these discrete and differential genes vs environmental interactions may not be readily captured in simple association studies. OBJECTIVE To determine whether children carrying the 7-repeat allele of the DRD4 gene living under adverse economic conditions have worse-than-average fat intake compared with those living in a healthy environment. DESIGN, SETTING, AND PARTICIPANTS Data from an established prospective birth cohort (Maternal Adversity, Vulnerability, and Neurodevelopment) were used to study 4-year-old children from Montreal, Quebec, Canada and Hamilton, Ontario, Canada. A total of 190 children (94 girls and 96 boys) had height and weight measured and complete food diaries and were therefore eligible for the study. The study is derived from a birth cohort started in June 2003 and still ongoing. The last age of follow-up was at 6 years. EXPOSURES Social environment was characterized based on the gross family income, and DNA was genotyped for the 7-repeat allele of the DRD4 gene. MAIN OUTCOMES AND MEASURES Fat intake. RESULTS The 5 steps to distinguish the differential susceptibility from other types of interaction were followed, and the study confirms that differential susceptibility is a relevant model to address the association between the 7-repeat allele of DRD4 and food choices in girls. Of the 190 children, 112 did not have the DRD4 7-repeat allele and 78 did. Baseline characteristics did not differ in these 2 groups. Although not different in several confounders, such as maternal educational level, maternal smoking during gestation, birth weight, and breastfeeding duration, girls carrying the 7-repeat allele of the DRD4 gene and living in adverse socioeconomic conditions have increased fat intake compared with girls who are noncarriers (DRD4 7+ mean, 33.95% of calories derived from fat; 95% CI, 28.76%-39.13%; DRD4 7- mean, 28.76%; 95% CI, 26.77%-30.83%). However, girls carrying the 7-repeat allele of the same gene and living in better socioeconomic conditions have decreased fat intake compared with noncarriers (DRD4 7+ mean, 29.03% of calories derived from fat; 95% CI, 26.69%-31.51%; DRD4 7- mean, 31.88%; 95% CI, 30.28%-33.58%). CONCLUSIONS AND RELEVANCE Alleles previously considered to be obesity risk alleles might in fact function as plasticity alleles, determining openness to environmental modification and/or intervention, as seen in the girls in this study. This finding has important implications for obesity prevention and social pediatrics.

Gender differences in the association between stop-signal reaction times, body mass indices and/or spontaneous food intake in pre-school children: an early model of compromised inhibitory control and obesity.

Background:Poor inhibitory control is associated with overeating and/or obesity in school-age children, adolescents and adults. The current study examined whether an objective and reliable marker of response inhibition, the stop-signal reaction time (SSRT), is associated with body mass index (BMI) z-scores and/or food intake during a snack test in pre-school children.Methods:The current sample consisted of 193 pre-school children taking part in a longitudinal study of early brain development (Maternal Adversity, Vulnerability and Neurodevelopment (the MAVAN project)). Linear mixed-effect models were used to examine whether the SSRT measured at age 48 months associated with BMI z-scores and/or dietary intake during a laboratory-based snack test.Results:After controlling for significant covariates including maternal BMI, there was a significant gender by SSRT interaction effect in predicting 48-month BMI z-scores. Post-hoc analysis revealed an association between longer SSRTs (poor response inhibition) and higher BMIs in girls but not boys. Across both girls and boys, longer SSRTs were associated with greater intake of carbohydrates and sugars during the snack test. The association between SSRT scores and BMI z-scores in girls was not statistically mediated by carbohydrate or sugar intake.Conclusions:At 48 months of age, slower response inhibition on the Stop-Signal Task associates with higher BMI z-scores in girls, and with higher intake of carbohydrates and sugars during a snack test across both genders. Ongoing follow-up of these children will help clarify the implications of these associations for longer term macronutrient intake, eating-related pathology and/or pathological weight gain over time.

The interplay of birth weight, dopamine receptor D4 gene (DRD4), and early maternal care in the prediction of disorganized attachment at 36 months of age.

Disorganized attachment is an important early risk factor for socioemotional problems throughout childhood and into adulthood. Prevailing models of the etiology of disorganized attachment emphasize the role of highly dysfunctional parenting, to the exclusion of complex models examining the interplay of child and parental factors. Decades of research have established that extreme child birth weight may have long-term effects on developmental processes. These effects are typically negative, but this is not always the case. Recent studies have also identified the dopamine D4 receptor (DRD4) as a moderator of childrearing effects on the development of disorganized attachment. However, there are inconsistent findings concerning which variant of the polymorphism (seven-repeat long-form allele or non-seven-repeat short-form allele) is most likely to interact with caregiving in predicting disorganized versus organized attachment. In this study, we examined possible two- and three-way interactions and child DRD4 polymorphisms and birth weight and maternal caregiving at age 6 months in longitudinally predicting attachment disorganization at 36 months. Our sample is from the Maternal Adversity, Vulnerability and Neurodevelopment project, a sample of 650 mother-child dyads. Birth weight was cross-referenced with normative data to calculate birth weight percentile. Infant DRD4 was obtained with buccal swabs and categorized according to the presence of the putative allele seven repeat. Macroanalytic and microanalytic measures of maternal behavior were extracted from a videotaped session of 20 min of nonfeeding interaction followed by a 10-min divided attention maternal task at 6 months. Attachment was assessed at 36 months using the Strange Situation procedure, and categorized into disorganized attachment and others. The results indicated that a main effect for DRD4 and a two-way interaction of birth weight and 6-month maternal attention (frequency of maternal looking away behavior) and sensitivity predicted disorganized attachment in robust logistic regression models adjusted for social demographic covariates. Specifically, children in the midrange of birth weight were more likely to develop a disorganized attachment when exposed to less attentive maternal care. However, the association reversed with extreme birth weight (low and high). The DRD4 seven-repeat allele was associated with less disorganized attachment (protective), while non-seven-repeat children were more likely to be classified as disorganized attachment. The implications for understanding inconsistencies in the literature about which DRD4 genotype is the risk direction are also considered. Suggestions for intervention with families with infants at different levels of biological risk and caregiving risk are also discussed.

Maternal childhood adversity and child temperament: An association moderated by child 5-HTTLPR genotype

We examined transgenerational effects of maternal childhood adversity on child temperament and a functional promoter polymorphism, 5‐HTTLPR, in the serotonin‐transporter gene (SLC6A4) as potential moderators of such maternal influences in 154 mother–child dyads, recruited into a longitudinal birth cohort study. We examined the interactive effects of maternal childhood experience using an integrated measure derived from Childhood Trauma Questionnaire (CTQ) and Parental Bonding Index (PBI). Triallelic genotyping of 5‐HTTLPR was performed. A measure of ‘negative emotionality/behavioural dysregulation’ was derived from the Early Childhood Behaviour Questionnaire at 18 and 36 months. Negative emotionality/behavioural dysregulation was highly stable between 18 and 36 months and predicted psychosocial problems at 60 months. After controlling multiple demographics as well as both previous and concurrent maternal depression there was a significant interaction effect of maternal childhood adversity and offspring 5‐HTTLPR genotype on child negative emotionality/behavioural dysregulation (β = 1.03, t11,115 = 2.71, P < .01). The results suggest a transgenerational effect of maternal developmental history on emotional function in the offspring, describing a pathway that likely contributes to the familial transmission of vulnerability for psychopathology.

Attachment disorganization among children in Neonatal Intensive Care Unit: Preliminary results

BACKGROUND Preterm children have been reported to be at higher risk to develop attachment insecurity. AIMS The present study aimed to investigate potential differences in attachment security between newborns who were sent to Neonatal Intensive Care Unit (NICU) and those who were not, in a population of full-term children. STUDY DESIGN Participants (162 mother-child dyads) were part of a longitudinal study (MAVAN). Twenty-three of these children received special care at birth (NICU group). Attachment security was assessed at 36 months with the Strange Situation Procedure. Socio-economic status (SES), birth weight, maternal mood, maternal sensitivity, mental/psychomotor developmental indexes, Apgar scores, presence of complications during delivery and infant general health were assessed. RESULTS In the No-NICU group, 55.4% of children were securely attached, 24.5% were insecure and 20.1% were disorganized. However, in the NICU group, 43.5% of children were securely attached, 8.7% were insecure and 47.8% were disorganized (χ(2)=9.0; p=.01). The only differences between the 2 groups were a lower Apgar, more respiratory infections and more visits to walk-in clinic/hospital (ps<.05) and a trend for lower SES and more ear infections in the NICU group. Logistic regressions revealed an odds ratio of 6.1 (p=.003) of developing a disorganized attachment after a stay in NICU, when controlling for these confounding variables. CONCLUSION Newborns who were admitted to NICU have an odds ratio of about 6 to develop a disorganized attachment at 36 months. These preliminary results support the importance of supportive parental proximity and contact with the infant in the NICU and possible after-care.

Effects of Genotype and Sleep on Temperament.

BACKGROUND AND OBJECTIVES: Sleep problems are frequent in young children; however, children vary in the degree to which they are affected by poor sleep quality. We investigated whether a polymorphism in the serotonin transporter gene, which is linked to emotional function, is a potential moderator of the influences of sleep duration on infant temperament using longitudinal data. METHODS: We examined the interactive effects of average sleep duration between 6 and 36 months of age and the 5-HTTLPR genotype on negative emotionality/behavioral dysregulation at 36 months in 209 children recruited into a longitudinal birth cohort study. Triallelic genotyping of 5-HTTLPR was performed by looking at SLC6A4 genotype, focusing on the serotonin transporter-linked polymorphic region (5-HTTLPR) including the SNP polymorphism (rs23351). Child sleep habits were assessed with a maternal self-report questionnaire. RESULTS: After controlling for demographics and both previous and concurrent maternal depression, multiple linear regression analyses revealed a significant interaction effect of average sleep duration for the first 3 years of life and 5-HTTLPR genotype on child negative emotionality/behavioral dysregulation such that the effects were exclusive to those with low-expressing 5-HTTLPR genotypes. CONCLUSIONS: The results suggest differential susceptibility to the effect of sleep duration early in life, which reiterates that the short allele of the 5-HTTLPR represents a marker of increased environmental sensitivity regarding emotional development. Differential susceptibility theory posits that certain factors may increase an individual’s susceptibility to the environment, in either a positive or negative fashion.

An Attachment-Based Model of the Relationship Between Childhood Adversity and Somatization in Children and Adults

Objective An attachment model was used to understand how maternal sensitivity and adverse childhood experiences are related to somatization. Methods We examined maternal sensitivity at 6 and 18 months and somatization at 5 years in 292 children in a longitudinal cohort study. We next examined attachment insecurity and somatization (health anxiety, physical symptoms) in four adult cohorts: healthy primary care patients (AC1, n = 67), ulcerative colitis in remission (AC2, n = 100), hospital workers (AC3, n = 157), and paramedics (AC4, n = 188). Recall of childhood adversity was measured in AC3 and AC4. Attachment insecurity was tested as a possible mediator between childhood adversity and somatization in AC3 and AC4. Results In children, there was a significant negative relationship between maternal sensitivity at 18 months and somatization at age 5 years (B = −3.52, standard error = 1.16, t = −3.02, p = .003), whereas maternal sensitivity at 6 months had no significant relationship. In adults, there were consistent, significant relationships between attachment insecurity and somatization, with the strongest findings for attachment anxiety and health anxiety (AC1, &bgr; = 0.51; AC2, &bgr; = 0.43). There was a significant indirect effect of childhood adversity on physical symptoms mediated by attachment anxiety in AC3 and AC4. Conclusions Deficits in maternal sensitivity at 18 months of age are related to the emergence of somatization by age 5 years. Adult attachment insecurity is related to somatization. Insecure attachment may partially mediate the relationship between early adversity and somatization.

The joint contribution of maternal history of early adversity and adulthood depression to socioeconomic status and potential relevance for offspring development

BACKGROUND We examined the interactive effects of maternal childhood adversity and later adulthood depression on subsequent socioeconomic status (SES). METHODS Our community sample ranged from 230 to 243 mothers (across measures) drawn from a prospective, longitudinal cohort study. Maternal childhood adversity scores were derived using an integrated measure derived from the Childhood Trauma Questionnaire (CTQ) and the Parental Bonding Index (PBI). Maternal depression was measured in the prenatal period with the Center for Epidemiologic Studies Depression Scale (CES-D). SES measures included maternal highest level of education and family income as obtained prenatally. RESULTS The analyses yielded significant interaction effects between maternal childhood adversity and prenatal depression that predicted income, prenatally. Women who reported higher levels of childhood adversity combined with higher levels of self-reported depressive symptoms were significantly more likely to live in low SES environments. Results also showed that level of education was predicted by childhood adversity independent of maternal symptoms of depression. CONCLUSION The results suggest that SES is influenced by a life course pathway that begins in childhood and includes adversity-related mental health outcomes. Since child health and development is influenced by both maternal mental health and SES, this pathway may also contribute to the intergenerational transmission of the risk for psychopathology in the offspring. The results also emphasize the importance of studying potential precursors of low SES, a well-documented environmental risk factor for poor developmental outcomes in the offspring.

Prenatal maternal depression and child serotonin transporter linked polymorphic region (5-HTTLPR) and dopamine receptor D4 (DRD4) genotype predict negative emotionality from 3 to 36 months.

Prenatal maternal depression and a multilocus genetic profile of two susceptibility genes implicated in the stress response were examined in an interaction model predicting negative emotionality in the first 3 years. In 179 mother-infant dyads from the Maternal Adversity, Vulnerability, and Neurodevelopment cohort, prenatal depression (Center for Epidemiologic Studies Depressions Scale) was assessed at 24 to 36 weeks. The multilocus genetic profile score consisted of the number of susceptibility alleles from the serotonin transporter linked polymorphic region gene (5-HTTLPR): no long-rs25531(A) (LA: short/short, short/long-rs25531(G) [LG], or LG/LG] vs. any LA) and the dopamine receptor D4 gene (six to eight repeats vs. two to five repeats). Negative emotionality was extracted from the Infant Behaviour Questionnaire-Revised at 3 and 6 months and the Early Child Behavior Questionnaire at 18 and 36 months. Mixed and confirmatory regression analyses indicated that prenatal depression and the multilocus genetic profile interacted to predict negative emotionality from 3 to 36 months. The results were characterized by a differential susceptibility model at 3 and 6 months and by a diathesis-stress model at 36 months.