Are prenatal mercury levels associated with subsequent blood pressure in childhood and adolescence?:The Avon prebirth cohort study

OBJECTIVES: There have been conflicting data suggesting that prenatal mercury exposure is associated with adverse cardiovascular measures in children. We therefore analysed a large prospective population study to investigate whether prenatal mercury exposure might influence offspring blood pressure (BP) and heart rate adversely. DESIGN: Prospective birth cohort. SETTING: The Avon Longitudinal Study of Parents and Children (ALSPAC). PARTICIPANTS: Maternal whole blood collected in the first half of pregnancy was assayed for mercury and selenium. The offspring were followed throughout childhood and adolescence. OUTCOME MEASURES: Offspring resting BP and heart rates measured under standard conditions on six occasions between ages 7 and 17 years (numbers analysed: 1754 at 7 years to 1102 at 17). RESULTS: Statistical analyses took account of various factors present in pregnancy, including family adversity, maternal age, parity, smoking and alcohol intake. Unadjusted and adjusted regression analyses assessed the relationship between maternal prenatal mercury levels and offspring resting systolic and diastolic BP, and heart rates. A final set of analyses took account of selenium. Each analysis was carried out for all offspring, those whose mothers had, and those that had not, consumed fish during pregnancy. Further analysis for all offspring ascertained whether there were significant interaction effects between the sexes. There was little evidence to suggest that prenatal mercury exposure resulted in a clinically important increase in offspring BP in the whole group, since no effect size for an increase of 1 SD of blood mercury level was >0.3 mm Hg. Only 1 association was significant at p<0.05 and therefore likely due to chance. CONCLUSIONS: This study reveals no evidence to support the hypothesis that prenatal mercury exposure has adverse long-term effects on offspring BP or heart rates during childhood or adolescence

Dental associations with blood mercury in pregnant women

OBJECTIVES: There is curiosity concerning the source of mercury that is absorbed into the mother's blood and which may affect the developing fetus. This study therefore sets out to determine the extent to which dental amalgam (DA) may contribute to total blood mercury (TBHg) levels of pregnant women in the UK. METHODS: Whole blood samples and information on diet and socio‐demographic factors were collected from pregnant women (n = 4484) enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC). The whole blood samples were assayed for total mercury levels using inductively coupled plasma dynamic reaction cell mass spectrometry (ICP‐DRC‐MS), and the women were retrospectively asked about features of their dental care during the pregnancy. Linear regression was used to estimate the relative contributions of DA to TBHg levels (log‐transformed) based on R (2) values, compared to the results from dietary and socio‐demographic variables. RESULTS: The contribution to the variance of the mothers' TBHg levels by dental variables was 6.47%, a figure comparable to the 8.75% shown for seafood consumption in this population. Dietary and dental variables explained 20.16% of the variance, with socio‐demographic variables contributing only a further 3.40%. The number of amalgams in the mouth at the start of pregnancy accounted for most of the variance in dental variables. CONCLUSIONS: Dental amalgam contributes a comparable amount of variance in TBHg to seafood consumption in this population. However, because the measures of DA exposure were imprecise, these findings are likely to be an underestimate. There is no evidence to date in the literature that fetal exposures to mercury from maternal DAs have adverse effects on the developing child, but long‐term studies are warranted

Prenatal mercury exposure and offspring behaviour in childhood and adolescence

AbstractBackgroundThere is considerable discussion over the possible harm caused by fetal exposure to mercury, but evidence of such harm is contradictory at levels commonly found in populations with moderate intakes of fish. Further information is needed to inform debate and clarify policy recommendations.MaterialData were collected prospectively for the Avon Longitudinal Study of Parents and Children (ALSPAC). Whole blood taken in the first half of pregnancy was assayed for mercury. The outcomes were offspring behavioural assessments collected using the Strengths and Difficulties Questionnaire at seven time points between ages 4 and 16–17 years; five were completed by the mother and two by the teacher. Socioeconomic and biological confounders were first taken into account; further analyses added maternal blood selenium. Separate analyses compared the relationships between prenatal mercury levels and behaviour traits treated as continuous measures in women who ate fish with those who ate no fish in order to determine whether the relationships differed; the hypothesis was that fish consumption had benefits on the brain and masked any mercury effects. In order to prevent Type II errors, the P value for significance was set at 0.10.ResultsPrenatal mercury measurements and offspring behaviour results were available for between 2776 (at 47 months) to 1599 mother-child pairs (at 16–17 years). Even given a P value of 0.10, the number of significant results was no greater than expected apart from the relationships with peer problems at 4, 6 and 10–11 years where the relationships with prenatal mercury were negative (i.e. the greater the level of mercury the fewer the problems the child had with his/her peers). There were no significant differences between the associations with mercury found among the offspring of women who ate fish in pregnancy and those who did not, nor did adjustment for selenium make a difference.ConclusionsThere were no adverse effects of maternal prenatal mercury levels on the behaviour of the offspring. A similar lack of relationship was found when the analyses were confined to those offspring whose mothers had eaten fish in pregnancy, and no consistent differences were found between the fish and non-fish eaters

The Decrease of n-3 Fatty Acid Energy Percentage in an Equicaloric Diet Fed to B6C3Fe Mice for Three Generations Elicits Obesity

Feeding mice, over 3 generations, an equicaloric diet in which α-linolenic acid, the dietary precursor of n-3 polyunsaturated fatty acids, was substituted by linoleic acid, the dietary precursor of n-6 polyunsaturated fatty acids, significantly increased body weight throughout life when compared with standard diet-fed mice. Adipogenesis observed in the low n-3 fatty acid mice was accompanied by a 6-fold upregulation of stearyl-coenzyme A desaturase 1 (Scd1), whose activity is correlated to plasma triglyceride levels. In total liver lipid and phospholipid extracts, the sum of n-3 fatty acids and the individual longer carbon chain acids, eicosapentaenoic acid (20:5n3), docosapentaenoic acid (22:5n3), and docosahexaenoic acid (22:6n3) were significantly decreased whereas arachidonic acid (20:4n6) was significantly increased. In addition, low n-3 fatty acid-fed mice had liver steatosis, heart, and kidney hypertrophy. Hence, reducing dietary α-linolenic acid, from 1.02 energy % to 0.16 energy % combined with raising linoleic acid intake resulted in obesity and had detrimental consequences on organ function

Parental, prenatal, and neonatal associations with ball skills at age 8 using an exposome approach.

There is little consistency in the literature concerning factors that influence motor coordination in children. A hypothesis-free "exposome" approach was used with 7359 children using longitudinal information covering 3 generations in regard to throwing a ball accurately at age 7 years. The analyses showed an independent robust negative association with mother's unhappiness in her midchildhood (6-11 years). No such association was present for study fathers. The offspring of parents who described themselves as having poor eyesight had poorer ability. This hypothesis-free approach has identified a strong negative association with an unhappy childhood. Future studies of this cohort will be used to determine whether the mechanism is manifest through differing parenting skills, or a biological mechanism reflecting epigenetic effects

Reduction in behavior problems with omega-3 supplementation in children aged 8–16 years: A randomized, double-blind, placebo-controlled, stratified, parallel-group trial

Background: While limited evidence suggests that omega-3 supplementation may reduce antisocial behavior in children, studies have not reported on posttreatment follow-up and most treatment periods have been of short duration. This study tests the hypothesis that omega-3 supplementation over 6 months will reduce behavior problems in children both at the end of treatment and at 6 months post treatment. Methods: In this randomized, double-blind, placebo-controlled, stratified, parallel-group trial, a community sample of 8-16 year old children were randomized into a treatment group (N = 100) and a placebo-control group (N = 100). The supplementation consisted of a fruit drink containing 1 g/day of omega-3 or a placebo consisting of the same fruit drink without omega-3. Participants, caregivers, and research assistants were blinded to group assignment. The primary outcome measures of externalizing and internalizing behavior problems were reported by both caregivers and their children in a laboratory setting at 0 months (baseline), 6 months (end of treatment) and 12 months (6 months post treatment), together with the secondary outcome measures of parental antisocial behavior. Data were analyzed on an intention-to-treat basis including all participants. Trial registration: ClinicalTrials.gov: http://clinicaltrials.gov/ct2/show/NCT02016079? term=mauritius&amp;rank=2. Results: Significant group 9 time interactions were observed with the treatment group showing long-term improvements in child behavior problems. The average posttreatment effect size was d = À.59. Effects were documented for parent reports, but with the exception of proactive and reactive aggression, child-report data were nonsignificant. Parents whose children took omega-3 showed significant posttreatment reductions in their own antisocial and aggressive behavior. This improvement in caregiver behavior partly mediated the improvements observed in child behavior. Conclusions: Findings provide initial evidence that omega-3 supplementation can produce sustained reductions in externalizing and internalizing behavior problems. Results are the first to report improvements in caregiver behavior, and to establish this improvement as a part-mechanism for the efficacy of omega-3. Keywords: Omega-3, externalizing, internalizing, aggression, randomized trial. Introduction Poor nutritional status during pregnancy has been found to predispose to antisocial personality disorder in adulthood Given this nutrition -brain -antisocial behavior linkage, improving nutrition may help improve child behavior problems. Vitamin and mineral supplementation may reduce antisocial behavior, although evidence here is relatively sparse There are also methodological limitations in prior studies. Some are correlational, yet RCTs are the building blocks of evidence-based practice To help address these issues, this study&apos;s primary aim was to test whether omega-3 supplementation reduces child and adolescent antisocial/aggressive behavior. The main hypothesis was that omega-3 supplementation will reduce externalizing behavior problems both at the end of treatment and also 6-months post treatment. Secondary aims were to assess for reduction in internalizing behavior problems, and to examine any influence of nutritional supplementation to the child on their caregiver&apos;s antisocial behavior, and whether any such parental change could contribute to child behavior change. Methods Trial design The design consisted of a randomized, double-blind, placebo-controlled, stratified, parallel-group trial (1:1 ratio) of children in the community. Trial design remained unchanged throughout the study. Study setting The study took place in interview rooms at the Joint Child Health Project headquarters in Quatre Bornes, Mauritius, from November 2009 to December 2011. Further details of this country and past research can be found in Raine, Participants Participants consisted of 200 children of parents who themselves had participated in the Mauritius Child Health Project Reviews of RCTs have commented that median sample sizes in RCTs are relatively modest, with estimates of 46, 54, 65, and 80 from different reviews Omega-3 intervention Omega-3 supplementation. This consisted of a 200 ml drink (Smartfish Recharge). The base drink in both treatment and control conditions consisted of fruit juice from apple, pear, pomegranate, aronia, and passion fruit. It also contained vitamin D (0.85 lg) and antioxidants (ferric reducing ability of plasma value of 0.71 mmol/100 g). For the treatment condition only, a total of 1000 mg of omega-3 (300 mg of DHA, 200 mg of EPA, 400 mg of alpha-linolenic acid, and 100 mg of DPA) was added to the base drink. Placebo drinks were matched exactly with the fish-oil drink in terms of size, appearance, and flavor. This drink was chosen because: (a) it contains an appreciably higher dosage of omega-3 than standard capsules in a relatively small liquid quantity (60.6% of the size of a standard can of cola) suitable for child consumption, (b) the fruit-flavored drink may be better tolerated and result in higher compliance with children than standard capsules. Treatment duration and administration. Treatment duration was 6 months. This duration was chosen because prior treatment studies have usually been 2-4 months Outcome measures The predefined primary outcome measures were externalizing behavior problems including aggressive behavior. Secondary outcomes included internalizing behavior problems and parental aggressive and psychopathic behavior. Child behavior checklist (CBCL) and youth self report (YSR). The CBCL (parent report) and YSR (child report) are well-standardized, extensively used psychometric instruments with high reliability/validity in many countries Reactive-proactive aggression questionnaire (RPQ). Children completed this self-report instrument which yields scales of reactive, proactive, and total aggression Psychopathic personality inventory (PPI). Parents completed the short version of the self-report Psychopathic Personality Inventory (PPI -Lilienfeld &amp; Andrews, 1996). It yields a global psychopathy score, and eight subscales measuring social potency, cold-heartedness, fearlessness, impulsive nonconformity, stress immunity, Machiavellian egocentricity, blame externalization, and carefree nonplanfulness. The PPI was designed for use in nonclinical settings and has been shown to be reliable and valid in community samples Randomization and stratification After giving informed consent, participants were randomized into treatment and placebo groups with blocking on a 1:1 ratio (Suresh, 2011). Prior to initial group assignment, matched pairs of participants were created from the computer data--base, with matching on age band (8-10, 11-13, 14-16), gender (male/female), and ethnicity (Indian/Creole). This stratification procedure aims to balance groups on key demographic variables. Within each of the 100 pairs, restricted randomization to group was conducted using a computer-generated list of random numbers generated by SPSS. Adherence to protocol Adherence to the treatment regimen was assessed at the end of treatment by asking caregivers how often the drink had been consumed (number of drinks/week). Adherence was also assessed by assays of omega-6 and omega-3 from finger-prick blood taken at baseline and 6 months (end of treatment). For detailed methods see Lin, Loewke, Hyun, Leazer, and Hibbeln (2012). Statistical methods An intention-to-treat (ITT) design using all randomly assigned participants (200) was employed for all data analyses. Data missing due to loss at follow-up were imputed using the last observation carried forward strategy (White, Horton, &amp; Pocock, 2011). The ITT approach is considered a gold standard for RCTs, is endorsed by CONSORT, respects initial randomization, and provides unbiased estimates of the effect of treatment assignment on outcome measures Analyses focused on documenting group 9 time interactions, with effect sizes calculated using partial g 2 . Differences in baseline scores were compared using two-tailed independent t-test. Where differences were observed (only for child self-report RPQ), baseline scores were entered as covariates to equalize groups at baseline. To assess whether any improvement in parental behavior may partly account for the treatment effect on child behavior, mediation analyses were performed using the PROCESS SPSS macro Results Participant flow and recruitment Participant flow and recruitment details are outlined in the Supplemental Demographics and adherence to protocol Demographics. Demographic data are reported in Adherence to protocol. Average number of drinks taken per week for each group are provided in Child behavioral problems Means and SDs on parent and child outcome measures for children at all three time points, © 2014 Association for Child and Adolescent Mental Health. Child behavior problems and omega-3 supplementation 3 group 9 trial interactions, effect sizes for interactions and posttreatment group differences are detailed in Parent report. Significant group 9 time interactions were observed for all internalizing and externalizing subscales, except for somatic complaints. A significant interaction was also obtained for callous-unemotional traits. All other results were nonsignificant. Interactions for externalizing, internalizing, and callous-unemotional behavior are illustrated in Child report. In contrast to parent reports, for most self-report measures no group 9 trial interactions were observed. Significant interactions were, however, observed for self-report reactive (p &lt; .0001) and proactive (p = .02) aggression, as well as total aggression (p &lt; .0001). Both forms of aggression showed significant intervention declines only in the omega-3 group by the end of treatment at 6 months (average d = À.80, 95% C.I. = À1.08 to À.52) (see Parental antisocial behavior Means, SDs, group 9 time interactions, and posttreatment effect sizes are shown in For reactive aggression, all groups showed declines over time, but the within-group posttreatment decline was greater in the omega-3 group than in controls with respect to both 6-12 months within-group change scores (t = 2.15, df = 198, p = .04, d = À.30, CI = À.03 to À.58) and also 0-12 month change scores (t = 2.12, df = 198, p = .04, d = À.30, CI = À.02 to À.58). Groups did not differ from each other at the end point (12 months). Influence of placebo effects Because the above results documented a short-term placebo effect for parent reports of child behavior, groups were examined for differences in their belief in group assignment, and whether this could explain group differences in child behavior. By the end of treatment at 6 months, caregivers with children randomized into the treatment group were more likely to believe their children were receiving omega-3 (97%) compared to the placebo group (53%) (v 2 = 51.63, df = 1, p &lt; .0001, g = .51). To assess if this belief influenced parental perception of their child&apos;s behavior, this measure was entered as a covariate in all previously significant analyses. After controlling for parental belief in treatment allocation, the group 9 time interaction for parental reports remained significant for externalizing behavior (F[2,394] = 7.59, p = .001, g 2 = .04) and internalizing behavior (F[2,394] = 6.44, p = .002, g 2 = .03). All other previously significant findings remained significant (p &lt; .05). One previously nonsignificant interaction for narcissism became significant after controlling for parental belief (F[2,195] = 8.44, p = .048, g 2 = .02). Factors influencing improvement in parental behavior We tested whether improvements in the child&apos;s behavior at 12 months partly accounted for improvement in their parent&apos;s behavior at 12 months. Improvement in child callous-unemotional traits (indirect effect: b = .04, p &lt; .05), reactive aggression (indirect effect: b = .02, p &lt; .05), and total RPQ aggression (indirect effect: b = .02, p &lt; .05) all separately mediated improvement in parental psychopathy, but not parental reactive aggression. No other child improvements were found to mediate improved parental behavior (p &gt; .05). In total, improvement in child behavior following treatment accounted for 38.7% of the improvement in parental antisocial behavior. Adrian Raine et al. Child behavior problems and omega-3 supplementation 5 Adrian Raine et al. Factors accounting for improvement in child behavior Omega-3 treatment of the child was associated with improvements in their parent&apos;s behavior. Improved parental behavior may therefore partly account for the treatment effect on child behavior. Testing this hypothesis, changes in parental psychopathy partly mediated child treatment outcomes for callous-unemotional traits (indirect effect: b = .06, p &lt; .05), reactive aggression (indirect effect: b = .06, p &lt; .05), and total RPQ aggression (indirect effect: b = .06, p &lt; .05). Changes in parental reactive aggression partly mediated child treatment effects for anxious-depressed (indirect effect: b = .02, p &lt; .05). No other parental improvement mediated improved child behavior (p &gt; .05). In total, improvement in parental behavior accounted for 60.9% of the improvement in child antisocial behavior and 40.0% of the improvement in child anxious-depressed behavior. Adverse events No major adverse events were reported. Minor adverse events during the 6 month treatment period were reported by 17 parents (8.5%) and 6 children (3%) (see Discussion The study&apos;s main finding was that omega-3 supplementation for 6 months resulted in a 41.6% reduction in parent-rated child externalizing behavior half-a--year after treatment ended. A similar long-term reduction (68.4%) was observed for internalizing behavior. Results could not easily be attributed to placebo expectations. Findings are mitigated by the failure to observe similar effects for child self-reports, with the exception of significant short-term reductions in self-report child reactive (58.9% reduction) and proactive (49.7%) aggression. In the parents of treated children, significant reductions were also observed in parental psychopathy and reactive aggression. Improvement in parental behavior accounted for 60.9% of the improvement in child antisocial behavior. To our knowledge, this is the first study to document support for the longer-term posttreatment efficacy of omega-3 in reducing child and adolescent externalizing and internalizing behavior, and to document reduced antisocial behavior in caregivers. Improvements in child behavior problems In addition to significant improvements in aggressive and antisocial behaviors, the medium effect size (d = À.58) for long-term improvement in callous-unemotional traits is notable given the recent addition of this trait as a specifier in DSM-V (American Psychiatry Association, 2013) and the increasing interest in child psychopathic-like behavior While the primary focus of this study was on antisocial and aggressive behavior, positive treatment effects were also observed for almost all internalizing behavior problems. While omega-3 supplementation has been shown in some studies to reduce childhood depression (Nemets, Nemets, Apter, Bracha, &amp; Bel- Child behavior problems and omega-3 supplementation 7 Mechanisms of action While the study cannot identify proximal neurobiological mechanisms whereby omega-3 results in long-term reductions in externalizing behavior problems, callous-unemotional traits, and reactive/proactive aggression, this long-chain fatty acid plays a critical role in brain structure and function, making up approximately 35% of the cell membrane, enhancing neurite outgrowth, and regulating both neurotransmitter functioning and gene expression Placebo effects Improvements in child behavior were not explained by parent&apos;s belief in treatment allocation, with the group 9 time interaction effects remaining significant after controlling for this belief. On the contrary, effects for the narcissism component of the child psychopathy measure became significant after controlling for this confound. These findings dictate against a placebo effect as an explanation for the sustained improvement in child behavior over time. Nevertheless, the placebo group did show improvements during the initial test period up to 6 months on several outcomes. While expectation of improvement with treatment enrollment likely contributed to this effect, it is also conceivable that the antioxidants and vitamin D contained in the placebo drink may have contributed to this transient change given some evidence suggesting potential efficacy of micronutrient supplementation for antisocial behavior Reporter effects Improvement in child behavior following omega-3 consumption was observed for parent reports, but with the exception of proactive and reactive aggression, no effects were observed with child self reports. Similar results have been observed in other studies. The only two RCTs of omega-3 conducted in prison which documented behavioral improvement as monitored by others either failed to observe effects for self reports The fact that effects were nevertheless obtained for child self-reported proactive and reactive aggression Child behavior problems and omega-3 supplementation 9 may be due to the fact that in the construction of this self-report measure, it was argued that children know better than their parents the underlying motive for aggressive behavior, a factor critical for distinguishing goal-oriented proactive aggression from aggression in reaction to a provocation Study limitations and generalizability Regarding limitations, the ITT approach which analyzed all participants irrespective of treatment completion is viewed as an important defense against selection bias Caveats are also needed on generalizability of findings. While Mauritius is a developed country, future generalization to other countries and other ethnic groups is required. Furthermore, the research staff reported unusually strong enthusiasm to participate in this treatment study compared to the risk research normally conducted at the Joint Child Health Project. This again cautions against generalization of findings from this RCT to other international settings. Conclusions In conclusion, this RCT shows that 6 months of omega-3 supplementation in fruit juice drink form results in a 42-68% reduction in parent-reported externalizing and internalizing behavior problems in community-residing children and adolescents, with improvement continuing 6 months after treatment cessation. While replication and generalization to other countries is critical, the potential clinical promise is that these nutrients can shift the distribution of behavior problems to a lower level in the general population and that more severe behavioral problems that are significant risk factors for serious adult violence and psychopathology may be ameliorated. Supporting information Additional Supporting Information may be found in the online version of this article: Acknowledgements This study was made possible in part by funding from Smartfish AA, Oslo, Norway, who produced the omega-3 supplement and placebo drink used in this study. It was also supported in part by the Intramural Research Program of the National Institute on Alcohol Abuse and Alcoholism, Rockville, MD, and the University of Pennsylvania. The authors wish to thank Shameem Oomur, Shameemah Golamnobee, and Joelle Rawoteea for their assistance in data collection. The authors have declared that they have no competing or potential conflicts of interest. Correspondence Adrian Raine, Departments of Criminology, Psychiatry, and Psychology, University of Pennsylvania, 3809 Walnut Street, Philadelphia, PA 19104, USA; Email: araine @sas.upenn.edu Key points • It is unclear whether omega-3 supplementation can reduced externalizing and internalizing behavior problems in child and adolescent populations. • This RCT showed that 6 months of omega-3 supplementation in fruit juice form produced long-term posttreatment reductions in parent-reported externalizing behavior problems (41.6%) and internalizing behavior problems (68.4%). • Caregivers of children receiving omega-3 also showed significant reductions in their own antisocial behavior. • Improvements in parental behavior accounted for 60.9% of the improvement in child behavior. • This is the first study to report not just posttreatment reductions in child antisocial behavior, but also to document improvements in parental behavior that in part explain treatment efficacy

Maternal fish consumption during pregnancy and smoking behavioural patterns

Abstractn-3 Highly unsaturated fatty acids (HUFA), are essential components of neuronal membranes and mediate a range of complex bioactive properties including gene expression, myelination, cell-signalling and dopaminergic function. Deficits inn-3 HUFA have been linked to increased risks for addictive disorders, thus we posited that lower fish consumption would be associated with greater risks for perinatal smoking among 9640 mothers enroled in the Avon Longitudinal Study of Parents and Children. We used univariable and multivariable regression models to examine relationships between self-reported prenatal dietary intakes ofn-3 HUFA-rich foods (fish and shellfish) and maternal smoking; outcomes included cessation and the number of cigarettes smoked per d. Both before and during pregnancy, there was consistent evidence (P&lt;0·001) of protective fish intake–smoking associations; relative to mothers reporting no fish consumption, those who reported some fish consumption (&lt;340 g/week) and high fish consumption (340 g+/week) at 32 weeks of gestation showed lower likelihoods of smoking (adjustedPvalues &lt;0·001). Respective OR for these relationships were 0·87 (95% CI 0·77, 0·97) and 0·73 (95% CI 0·61, 0·86). Although the prevalence of smoking diminished, from a high of 31·6% (pre-pregnancy) to a low of 18·7% (second trimester), the magnitude of fish intake–smoking associations remained stable following adjustment for confounders. These observations suggest that greater fish orn-3 HUFA consumption should be evaluated as an intervention to reduce or prevent smoking in randomised clinical trials.</jats:p