Advances in Understanding the Relationship between Child Problem Behavior and Maternal Long-Chain PUFA Intake

This article at a glance
  • An important area in omega-3 research addresses the possibility to prevent or alleviate ADHD in childhood by omega-3 supplementaton with omega-3 LCPUFA of mothers during pregnancy or the children with ADHD themselves.
  • A higher n-3:n-6 ratio during mid-pregnancy was found to be associated with fewer emotional, but not behavioral, problems in six-year old children.
  • In a randomized double-blind placebo-controlled intervention trial with 8-14 year old boys with ADHD it was found that attention levels improved in boys that received omega-3 LCPUFA supplementation for four months.
  Introduction Understanding to what extent and how maternal omega-3 long-chain polyunsaturated fatty acid (omega-3 LCPUFA) intake during pregnancy and lactation determines the growth and development of the fetus and newborns has fascinated nutrition researchers from the time these fatty acids were recognized to be essential for human health. This consideration has also expanded into understanding if maternal omega-3 LCPUFA availability determines the emotional well-being and behavior of children at later ages. This interest stems from the fact that omega-3 LCPUFA contribute to a significant extent to membrane lipid structure and function in the central nervous system. Docosahexaenoic acid (DHA) in particular is one of the major PUFA within membrane lipids in brain tissue, imparting functional properties to neuronal cells, glial cells and the blood-brain barrier, allowing control over regulation of immune privilege, cellular viability, neuroplasticity and neurotransmission. The availability of LCPUFA for fetal and infant brain development depends nearly exclusively on maternal fatty acid provision via placental transfer in utero and breast milk after birth. Recommendations for adequate intake of PUFA during pregnancy and the post-natal period are hence updated periodically. DHA and arachidonic acid (AA) are now routinely added to infant formula. Early perinatal nutritional inadequacies that determine behavioral and emotional well-being at later ages (toddler, school-age and adult), and that are modifiable by relatively simple dietary changes of the mother or via infant formulae, are of significant relevance to individuals, parents, and to society at large. Furthermore, the possibility to correct any long-term emotional and cognitive effects of maternal nutritional deficits in omega-3 LCPUFA by supplementation is also an important therapeutic option to assess. Several studies in humans have pointed out a direct relationship between neurocognitive deficits in childhood or adult life and low blood levels of omega-3 LCPUFA and/or increased ratio of omega-6 to omega-3 LCPUFA during pregnancy. However, most of the evidence linking perinatal nutritional inadequacy and later life cognitive and behavioral deficits originates from animal studies. A number of studies have indicated that emotional and cognitive deficits in school age and adult life can be attenuated by increased omega-3 LCPUFA intake via the diet or supplementation with omega-3 LCPUFA. Steenweg de Graaf Bos 1Behavioral disruption in children is often associated with attention deficit/hyperactivity disorder or ADHD, a disorder with varying signs and symptoms that encompass several of the following: children with ADHD may be clumsy and accident-prone, show erratic and disruptive behavior (fits and tantrums), compulsively touch everything and everyone, are in constant motion, disturb other children and may be aggressive and argumentative, are unable to concentrate, fail to finish activities or tasks, are easily frustrated, are easily distracted and often unable to follow instructions, lack social skills, have a normal or high IQ but may do badly at school, have poor hand and eye coordination, and are uncooperative, defiant and disobedient. ADHD has an estimated prevalence of 7.5% among children worldwide according to a recent systematic analysis. It has been suggested that the prevalence of ADHD is increasing in developed countries but this has not been substantiated. Renewed research is focusing on determining the effectiveness of dietary adequacy of omega-3 LCPUFA in children affected by ADHD. The results of studies carried out to address the long-term effects of maternal nutritional inadequacy or nutritional intervention studies in ADHD are not unambiguous. The variability in study design and target groups may have contributed to this. Foremost, many cohort studies have been relatively small and underpowered to have properly detected any effects. Additionally, scoring of the variable displays of emotional and behavioral problems is difficult, and most studies rely on measurements from one setting, for example at home or at school, but not in both places. A recent open intervention trial has reported that omega-3 LCPUFA supplementation may be beneficial in children with ADHD that were also being treated with methylphenidate. Also recent meta-analyses of interventional studies have concluded that omega-3 LCPUFA supplementation in ADHD may be modestly efficacious. Study Examines Effects in Six-Year Olds In a recently published study, Steenweg-de Graaf and colleagues addressed associations between maternal LCPUFA status during pregnancy and emotional and behavioral problems in six-year old children. The study is part of a larger initiative called the Generation R Study, which is following the development of 10,000 children in the city of Rotterdam, The Netherlands. This study was performed by researchers from the Generation R Study Group and various departments at the Erasmus Medical Center in Rotterdam, The Netherlands, and the Dr. von Hauner Children’s Hospital in Munich, Germany. The population-based study involved 6916 mother-child dyads, and measured several parameters related to child behavior and emotions at six years of age scored by both parents and teachers. At least one measure of child behavior at age six was available for 5307 children. Venous samples drawn at mid-pregnancy (median week 20.5) were analyzed for arachidonic acid (AA), EPA and DHA, and n-3:n-6 ratio, present in plasma phospholipids. The Child-Behavior Checklist (CBCL) questionnaire was filled out by parents to measure the degree of children’s problem behavior in the preceding two months, and was compared to the known distribution in the population to assign a cut-off definition for problematic behavior. In this study the so-called CBCL 11/2-5 questionnaire was used since a substantial part of the children had not yet turned six. The CBCL makes possible the calculation of a value for emotional and behavioral problems by rating a large series of problem items. This type of scoring makes possible the ranking of various problems, typical of disrupted children’s emotions and behavior in ADHD. Steenweg de Graaf Bos - Fig 1A second test was a version of the CBCL called TRF 6-18, for behavioral and emotional problems scored by the teachers of the studied children. Of importance, recovering information in different contexts, such as home and school, provides complementary information, which may be lost in studies that focus on one context alone. Parent and teacher scores were examined individually and combined. In a subset of children with higher scores on the CBLC scale (>85th percentile) a diagnosis of problem behavior was obtained with a parent-administered interview (DISC-YM or Diagnostic Interview Schedule, Young Children). This highly structured computerized test generates diagnoses on anxiety disorders, mood (emotional) disorders, and behavioral disorders. When child and maternal characteristics were stratified by maternal n-3:-6 ratio in mid-pregnancy, it was found that a number of variables differed significantly. For example, children of mothers with the lowest quintile n-3:n-6 ratio had a lower birth weight, spent half the time in daycare, and had a higher dietary intake of omega-6 PUFA at 14 months (compared to all other quintiles combined). Mothers in this lowest quintile were of significantly different non-European ethnic background, had received fewer years of higher education, had a lower average family income, presented with a higher level of general psychiatric symptoms during pregnancy, were more likely to have smoked and less likely to have consumed alcohol during pregnancy. When children-mother dyads of the 208 children that were found to have emotional and behavioral problems were compared to the other mother-child pairs, a number of differences were observed. Firstly, the children in this group contained a lower number of girls, and were less likely to have attended daycare. Of their mothers, fewer were of European ethnicity, fewer had completed higher education, they had a lower average income, they presented with a marked increase in psychiatric symptoms in mid-pregnancy, they were more likely to have smoked during pregnancy, less likely to drink alcohol, and fewer mothers were married. Results Steenweg de Graaf Bos 2Parent report of child emotional problems was significantly lower in children whose mothers had a higher maternal DHA level (odds ratio OR 0.82). This was also found when the reporting by parents and teachers was combined (OR 0.79). The n-3:n-6 ratio was significantly inversely associated with parent and combined parent-teacher reporting of emotional problems (OR 0.83 and 0.77, respectively). Teachers reporting alone did not reveal any significant differences in emotional problems. Use of the parent-scored DISC-YM testing method did not reveal any significant differences in emotional problems in the sub-group of children enriched for having emotional and behavioral problems. With respect to behavioral problems, parent-report did not identify any significant associations between maternal PUFA status during pregnancy and their children’s behavior. However, teacher’s report showed a significantly increased probability for having behavioral problems associated with increased maternal blood phospholipid levels of AA (OR 1.10), DHA (OR 1.23), as well as the n-3:n-6 ratio (OR 1.23). The combined teacher-parent report also identified a positive relationship between AA and behavioral problems. Again, no significant association between maternal PUFA status and behavioral problems were identified by the DISC-YM testing method. When the maternal n-3:n-6 ratio was stratified by quintiles, marked differences in the probability to suffer emotional, but not behavioral, problems in the offspring were identified (using parent report of child problem behavior). Compared to the lowest quintile, the three highest quintiles displayed odds ratios of 0.58, 0.39 and 0.35 (after correction for a number of covariates such as gestational age at blood sampling, sex, and age of child at assessment). After correction for additional covariates (such as family income, educational level, European origin, psychiatric symptoms in mid-pregnancy, smoking and alcohol consumption during pregnancy, age at enrollment, parity, marital status, and child care attendance), the odds ratios for the two highest quintiles remained significantly different from the lowest quintile (0.62 and 0.61). In summary, the results of this cross-sectional study in Dutch six-year old children from a multi-ethnic city suggest that a higher n-3:n-6 ratio during mid-pregnancy of their mothers is predictive for having fewer emotional problems. In particular DHA may contribute to this association. This does not apply to behavioral problems, where no association with LCPUFA status was identified. In contrast, a small increase in behavioral problems by teacher’s reporting was found to be associated with an increased maternal AA and DHA level, as well as with an increased n-3:n-6 ratio. The limitations and virtues of this study are both related to the comprehensive nature of the reporting, where different symptom scoring approaches, and scoring ADHD symptoms in different physical environments, do not appear to provide the same information. This study hence provides important guidance for future studies, as it points out that limiting reporting to a single approach and environment is unlikely to provide a good view of ADHD in children in this age group. A positive association between a higher n-3:n-6 ratio and behavioral problems, and with seemingly incompatible increased DHA and AA levels at the same time, suggests that other omega-3 PUFA or other omega-6 LCPUFA such as linoleic acid, might also contribute to these observations. Future research is needed to better understand in detail the associations between behavioral and emotional problems and individual fatty acids and fatty acid classes. Non-recognized covariates may also be important. Importantly, the population size in this study permits identifying meaningful associations. A Controlled Trial with ADHD Boys A second recently published study reports a randomized, double-blind, and placebo-controlled trial that addressed the effect of omega-3 LCPUFA supplementation during 16 weeks in 8-14 yr-old boys with clinically-diagnosed ADHD on ADHD symptoms and cognitive control. The study was performed by Bos and colleagues from the Department of Psychiatry at the Rudolf Magnus Brain Center, University Medical Center, in Utrecht, The Netherlands, the Wilhelmina Children’s Hospital in Utrecht, Dr. von Hauner Children’s Hospital in Munich, Germany and Unilever Research & Development in The Netherlands. Forty boys with ADHD were allocated in a masked and random 2x2 factorial design to one of two groups. The first group received supplementation with EPA and DHA as part of a margarine spread containing 650 mg EPA and 650 mg DHA per 10 g serving or a control margarine without EPA and DHA. Two further groups comprised boys (n=39; reference) without ADHD and matched in age, handedness, and body mass, allocated to EPA and DHA or a placebo margarine. Total intake and compliance was calculated from left-over margarine on a monthly basis, as well as daily recordings of margarine consumption by both parents and participants. Parents were masked to the test products. The boys otherwise continued their regular diets, fish consumption was limited to once a week, and no other use of omega-3 supplements was permitted. Boys with ADHD were allowed to continue any ongoing treatment with methylphenidate as a psychostimulatory medication. Before and after the intervention study, samples from buccal cheek tissue were collected, and the PUFA composition of phospholipids determined. Urine was collected in order to measure homovanillic acid excretion (as a measure for dopamine formation and breakdown). The severity of ADHD symptoms was assessed with two tests. The CBCL was used as the primary outcome, and was tested before and after the trial. The Strengths and Weaknesses of ADHD symptoms and Normal behavior scale (SWAN) test were used to collect results over the course of the trial. A teacher reporting test was used but did not receive sufficient feedback, and hence this study was limited to parental reporting. A Go/NoGo test was used as a cognitive control task before and after the trial to measure brain activation by functional magnetic resonance neuroimaging (fMRI), allowing the measurement of any changes in cognitive task performance and brain activation. Results Steenweg de Graaf Bos 4Supplementation with EPA and DHA for 16 weeks led to a significant improvement in parent-rated symptoms of inattention in the boys with ADHD (CBCL score changed from 9.1 to 7.7). In the boys in the reference group, with much lower baseline scores for attention problems (CBCL ~2.6) than boys with ADHD, it was noted that EPA and DHA supplementation might stabilize the development of behavioral problems during the course of the trial. These changes were accompanied by significant increases in cheek phospholipid DHA levels in boys that had received EPA and DHA supplementation, whereas they decreased in the reference groups over this period. A negative correlation was identified in boys with ADHD between their cheek DHA levels and attention problems, both before supplementation and after supplementation. No significant effect of EPA and DHA intake was found in rule-breaking behavior, aggressive behavior, or overall ADHD score. The absence of any effect of EPA and DHA supplementation on cognitive control measured by task performance and fMRI, or on dopamine turn-over calculated from homovanillic acid to creatinine ratios in urine, did not support an effect on cognitive control in boys with ADHD. Discussion The two new studies provide important new indications about the potential relationship between essential fatty acid intake and tissue status, and the incidence of emotional and behavioral problems in school age children. Importantly, the studies highlight a suitable way forward in addressing these topics, since they have addressed some methodological limitations of previous studies. Firstly, cross-sectional studies need to be large enough to enable measuring outcomes with sufficient power. Secondly, it is important that information on emotional and behavioral problems is scored in the different environments where children spend their time and may express themselves differently, for example at home versus school. The study nicely reflects this, with parent reporting giving different outcomes from teacher reporting. Whereas this makes assessment of interventional strategies and cohort studies in ADHD more difficult to conduct, it will likely be needed to obtain better insight into the complicated symptoms of this disorder. This limitation is already apparent, as teachers’ feedback was insufficient to evaluate results for all children in the second study. A randomized controlled trial can, however, provide information on direct causality and shows that four-month supplementation may help boys with ADHD recover attention level. An indication for a preventive activity on attention problems may also be apparent in normally developing boys, suggesting that basal intake of EPA and DHA could be very important in 8-14 year old boys. It is possible that measurable emotional problems may be avoided in children if the mother attains sufficiency in omega-3 PUFA during pregnancy, in particular with respect to DHA. Further research is necessary to confirm these important findings.   Bos DJ, Oranje B, Veerhoek ES, van Diepen RM, Weusten JMH, Demmelmair H, Koletzko B, de Sain-van der Velden MGM, Eilander A, Hoeksma M, Durston S. Reduced symptoms of inattention after dietary omega-3 fatty acid supslementation in boys with and without attention deficit/hyperactivity disorder. Neuropsychopharmacol. 2015;April 22:1-9. [PubMed] Steenweg-de Graaff JCJ, Tiemeier H, Basten MGJ, Rijlaarsdam J, Demmelmair H, Koletzko B, Hofman A, Jaddoe VWV, Verhulst FC, Roza SJ. 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