Critical Reviews in Food Science and Nutrition

ISSN: 1040-8398 (Print) 1549-7852 (Online) Journal homepage: www.tandfonline.com/journals/bfsn20

The role of marine omega-3 in human

neurodevelopment, including Autism Spectrum
Disorders and Attention-Deficit/Hyperactivity
Disorder – a review

Bárbara P. Martins, Narcisa M. Bandarra & Margarida Figueiredo-Braga

To cite this article: Bárbara P. Martins, Narcisa M. Bandarra & Margarida Figueiredo-Braga
(2020) The role of marine omega-3 in human neurodevelopment, including Autism Spectrum
Disorders and Attention-Deficit/Hyperactivity Disorder – a review, Critical Reviews in Food
Science and Nutrition, 60:9, 1431-1446, DOI: 10.1080/10408398.2019.1573800

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CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION
2020, VOL. 60, NO. 9, 1431–1446
https://doi.org/10.1080/10408398.2019.1573800

REVIEW

The role of marine omega-3 in human neurodevelopment, including Autism

Spectrum Disorders and Attention-Deficit/Hyperactivity Disorder – a review
B
arbara P. Martinsa, Narcisa M. Bandarrab , and Margarida Figueiredo-Bragaa,c
a
Department of Clinical Neurosciences and Mental Health, Medical Psychology, Faculty of Medicine, University of Porto, Porto, Portugal;
b
Department of Sea and Marine Resources, Portuguese Institute for the Sea and Atmosphere (IPMA, IP), Lisbon, Portugal; cResearch Group:
Metabolism, Nutrition & Endocrinology, i3S Instituto de Investigaç~ao e Inovaç~ao em Sa
ude, Porto, Portugal

ABSTRACT KEYWORDS
Autism Spectrum Disorders (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) are two Neurodevelopment; docosa-
increasingly prevalent neurodevelopmental disorders. This rise may be associated with a higher hexaenoic acid; n-3
dietary intake of n-6 polyunsaturated fatty acids (PUFAs) and lower of n-3 PUFAs. Polyunsaturated Fatty Acids;
maternal seafood intake;
Docosahexaenoic acid (DHA), a key nutritional n-3 PUFA, is crucial for an optimal offspring’s neuro- pregnancy; lactation
development through the last trimester of pregnancy. Recently, lower DHA levels have been
reported in children with ASD and ADHD. The present review summarizes the main research
achievements concerning the effect of DHA in children neurodevelopment, in order to elicit its
role in the prevention and mitigation of ASD and ADHD. As main finding, a low DHA supply
seems to negatively affect childhood neurodevelopment in specific conditions and increase the
risk and the severity of ASD or ADHD. Higher DHA status at birth was associated with better child-
hood neurodevelopmental, but controversial results found in prenatal supplementation raised the
hypothesis that the benefits of DHA may be influenced by other factors as socio-economic back-
ground and life-style. In conclusion, an optimal DHA provision through maternal diet or breastfeed
may promote some neuronal protection in specific offspring’s populations, suggesting that DHA
may act as a modifiable risk factor for ASD and ADHD.

Introduction et al. 2016). Advanced parental age and birth complications

related to ischemia, trauma and hypoxia have shown solid
Autism Spectrum Disorders (ASD) and Attention-Deficit/
links to ASD (Modabbernia, Velthorst, and Reichenberg
Hyperactivity Disorder (ADHD) are two neurodevelopmen-
2017). Other pregnancy-related factors such as extremely
tal disorders, that evolve as a result of interactions between
preterm delivery, very low birthweight, maternal infection,
genetic and environmental factors (American Psychiatric
use of infertility treatments, maternal exposure to environ-
Association (APA) 2013; Modabbernia, Velthorst, and
Reichenberg 2017). mental pollutants or specific medications, maternal obesity
ASD displays deficits in social communication and recip- and diabetes have shown a less strong, but significant, asso-
rocal social interaction and restricted repetitive activities, ciation with the risk of ASD (Modabbernia, Velthorst, and
behaviors and interests, frequently starting before three years Reichenberg 2017).
of age (Faras, Al Ateeqi, and Tidmarsh 2010). In the Fifth Despite the growing research interest in ASD, ADHD
Edition of the Diagnostic and Statistical Manual of Mental remains the most studied pediatric mental disorder, affecting
Disorders (DSM-V), the terms Autistic disorder, Asperger 5–7% of children and being 3 times more frequent in boys
disorder, Childhood disintegrative disorder, and Pervasive (Cortese and Castellanos 2015; National Institute of Mental
developmental disorder – not otherwise specified are included Health, NIH 2016). It is defined by ongoing pattern of
in ASD, also called Pervasive Developmental Disorder (APA inattention, problems in controlling impulsive behaviors or
2013). One in each 68 children (1.5%) in United States was be overly active, with an onset at 7–12 years of age (APA
affected in 2012, 4.5 times more frequent in boys than girls 2013; Cortese and Castellanos 2015; NIH 2016). Like in
(Christensen et al. 2016). Others studies in Europe, Asia, and ASD, genetic factors play an important etiological role, but
North America reported a prevalence of ASD of 1–2% other external factors, such as alcohol, tobacco or toxins
(Centers for Disease Control and Prevention (CDC) 2016). exposure during pregnancy, emotional difficulties, premature
Although ASD is highly heritable (last estimates 38–54%), or post mature delivery, low birth weight and pre- or post-
environmental factors are crucial in its etiology, especially natal brain injury have been shown to contribute to ADHD
those affecting fetal and early-life development (Madore (Guney, Cetin, and Iseri 2015).

CONTACT Margarida Figueiredo-Braga [email protected] Department of Clinical Neurosciences and Mental Health, Medical Psychology, Faculty of
Medicine, University of Porto, Alameda Prof. Hern^ani Monteiro, Porto, 4200-319, Portugal.
Supplemental data for this article is available online at https://doi.org/10.1080/10408398.2019.1573800.
ß 2019 Taylor & Francis Group, LLC
1432 B. P. MARTINS ET AL.

The clinical and etiological similarities between the two connectivity compared to healthy controls, resulting in
diseases are remarkable and their prevalence identically has changes in many neurodevelopmental outcomes (Donovan
increased at an alarming rate (Dougherty et al. 2016). A and Basson 2017; Dougherty et al. 2016; Polsek et al. 2011).
change to a Western diet, characterized by an increase in In patients with ASD, some level of intellectual disability
dietary pro-inflammatory omega-6 polyunsaturated fatty is detected in 70% (Srivastava and Schwartz 2014), and
acids (n-6 PUFAs), through meat and processed food, and a about 5–44% could have a seizure disorder (Lee, Smith, and
decrease in anti-inflammatory omega-3 (n-3 PUFAs), pre- Paciorkowski 2015). Anxiety, delays in learning, attention,
sent mainly in seafood, caused a dramatic increase in the n- sensory processing and motor activity deficits may also be
6 to n-3 PUFA ratio from the optimal 1-2:1 of the present (CDC 2016).
Paleolithic diet to about 20-30:1 (Akerele and Cheema An early postnatal brain overgrowth, with an increase in
2016). This change could be one of the explanations for the head circumference, is one of the most important morpho-
increased prevalence of these diseases, as a high ratio seems logical changes reported in ASD brain (Donovan and
to be unfavorable for the proper function of central nervous Basson 2017; Dougherty et al. 2016; Hazlett et al. 2005;
system (Morgese and Trabace 2016; Van Elst et al. 2014). Polsek et al. 2011), described as a possible predictor of its
N-3 PUFAs play a central role in the brain function and diagnosis in infants of high risk families (Hazlett et al.
structure of the neuronal cell membranes, and also in the 2017). Anterior temporal region and frontal cortex appear to
development of myelin sheath and retina (Van Elst et al. be the most affected (Geschwind 2009), highlighting the
2014). In particular, Docosahexaenoic acid (DHA) consti- growth of prefrontal cortex – a crucial area in ASD and
tutes 90% of the n-3 PUFAs in the human brain and about ADHD physiopathology due to its role in attention, impulse
10–20% of total lipids (Weiser, Butt, and Mohajeri 2016), control and cognitive function (Dougherty et al. 2016). This
being associated with a number of positive effects on mater- overgrowth seems to persist up to 5–6 years of age, after
nal and infant health (Morgese and Trabace 2016). Higher which no important volume increase is denoted, probably
DHA intake appears to reduce the risk of schizophrenia, representing a deviated maturational trajectory in ASD brain
bipolar disorder, depression, anxiety, and behavior disorders, (Ecker 2017). However, focal areas of reduced gray matter’s
while suboptimal DHA levels seem to be a potentially risk volume, such as in fronto-striatal networks, and reduced
factor for mental illness (Bozzatello et al. 2016). white matter’s volume in cerebellum and cerebral fornices
DHA is quickly incorporated into the retina and brain ner- are also described in these children (Ismail et al. 2016).
vous tissue during the third trimester of pregnancy until two A problem in long-range connectivity is now known as
years of age (Cardoso, Afonso, and Bandarra 2017). Since the an emerging theory in ASD. Dinstein et al. (2011) showed
synthesis of DHA in fetus is low, maternal DHA intake and that toddlers with Autism displayed a weaker “functional
status, and placental function, are critical for its supply to the connectivity” between brain hemispheres in language areas
fetus (Larque et al. 2012). Several observational studies and (including the superior temporal gyrus and the inferior
randomized clinical trials showed that higher prenatal levels of frontal cortex), with an abnormal right lateralized processing
DHA might improve pregnancy outcomes, such as birthweight of language, present since the age of 14 months. Other stud-
and gestation duration, and offspring neurodevelopment ies have found a significantly reduction in the volume of
(Carlson et al. 2013; Larque et al. 2012; Meher et al. 2016; corpus callosum, the major white matter bundle in the brain
Ramakrishnan et al. 2010). However, neurodevelopmental (Dougherty et al. 2016; Frazier and Hardan 2009). Overall,
improvements, especially for cognitive function, remain con- ASD patients appear to have a reduction in long-range con-
troversial and need further clarification (Osendarp 2011). nectivity, but normal or increased short-range neuronal con-
PUFA levels in blood are considered consistent bio- nections, which could clarify some of their better processing
markers of their status (Mazahery et al. 2017). Considering functions, like visual perception or some attention to detail
that children with ASD and ADHD have lower DHA and (Baron-Cohen and Belmonte 2005).
lower total n-3 PUFA serum levels compared to neurotypical On the other hand, it has recently been discovered that
controls, the determination of whether maternal DHA intake cerebellum plays a role in cognitive functions, making it an
alters the risk for these diseases is a reasonable and inform- important research area for ASD and ADHD (Basson and
ative next step for research. The present paper reviews ASD Wingate 2013; Fatemi et al. 2012). Most of the studies have
and ADHD neuroanatomy and physiology, relating them to found a larger size of cerebellum in ASD children, particu-
marine n-3 PUFAs, especially DHA, from mother’s diet. It larly prominent in its posterior lobe (Donovan and Basson
also aims to review present knowledge about the impact of 2017; Polsek et al. 2011). Although vermis has already been
DHA levels in prenatal and postnatal neurodevelopment, reported as smaller or larger compared to controls (Polsek
especially in children at higher risk for these diseases, such et al. 2011; Stanfield et al. 2008), a consistent finding was a
as preterm and very low birth weight infants. significant lower number and size of Purkinje cells in post-
mortem studies (Stanfield et al. 2008; Won, Mah, and
Kim 2013).
Neurodevelopment and functionally brain changes
In these patients, there is also a hypoactivation in social
in ASD and ADHD
brain regions (important for facial recognition, empathy,
Several studies indicated that individuals with ASD and social cognition and behavior), including the inferior frontal
ADHD have differences in anatomy, function and brain gyrus, anterior insula, anterior cingulate cortex, interparietal
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1433

sulcus, fusiform gyrus and amygdala, with an enlargement ADHD were a reduction in Fractional Anisotropy (FA),
of this last region (Hadjikhani et al. 2007; Schumann et al. using diffusion tensor images (DTI). However, ASD and
2009). However, recent studies pointed out that the problem ADHD seem to have an overlap in the corpus callosum and
in ASD may not be the social isolation, but a difficulty in vermis cerebellar (lower volume in magnetic resonance
the separation of consciousness of self and others, as they imaging and decreased FA in DTI), and superior longitu-
showed an abnormal activation of the ventromedial pre- dinal fasciculus (reduced FA) abnormalities, supporting the
frontal cortex in non-self-performing tasks, while in idea that white matter integrity is also affected in ADHD
unaffected children it is only activated in self-referential (Dougherty et al. 2016; Wu et al. 2017). In ADHD, the
processing (Kennedy and Courchesne 2008). amygdala volume has already been reported as normal
Another topic of discussion is the neuroinflammatory or decreased; so, these authors pointed out that amygdala
phenomenon found in ASD, characterized by an activation could serve as a marker for discriminating both disorders
of microglia, higher pro-inflammatory cytokines brain levels, (Dougherty et al. 2016).
autoantibody generation, and increased blood-brain barrier Finally, ADHD patients have an abnormal neurotrans-
permeability, which favors the migration of leukocytes to mission with lower levels of norepinephrine (particularly in
brain tissue (Madore et al. 2016; Onore, Careaga, and predominantly inattentive ADHD) and dopamine (mainly in
Ashwood 2012; Rossignol and Frye 2014). Animal models predominantly hyperactivity-impulsive ADHD) (Morgese
showed that the exposure to toxic substances or infections and Trabace 2016). As these neurotransmitters are associ-
during pregnancy led to an activation of the maternal ated with reward processing, but not with the emotional
immune system and neuroinflammation in offspring, pre- dysregulation, some authors have suggested that serotonin
senting a negative impact on neurodevelopment and subse- neurotransmission is also altered in ADHD (Nikolas et al.
quently contributing to ASD (Patterson 2011). 2010). Serotonin also modulates dopamine release and its
Lastly, regarding the neurotransmission changes in ASD, interaction seems to affect impulsivity; however, further
the excitation/inhibition imbalance theory stands out (Polsek studies are needed to confirm its link to ADHD pathology
et al. 2011). These subjects have high glutamate (excitatory) (Nikolas et al. 2010).
(Shinohe et al. 2006) and low Gamma-Aminobutyric Acid
(GABA) (inhibitory) blood levels, and a decreased density of
The role of maternal DHA intake in offspring
GABAA receptors (Fatemi et al. 2009), with a possible rela-
neurodevelopment
tion between glutamate upregulation and ASD severity
(Shinohe et al. 2006). The serotonin and dopamine neuro- The human brain growth spurt begins in the third trimester
transmission are also altered in these patients. Some of them of pregnancy, at which point the fetal brain begins to accu-
have higher blood levels of serotonin, which can impair lan- mulate DHA (Dagai, Peri-Naor, and Birk 2009; Janssen and
guage learning and intelligence quotient (IQ) level and pro- Kiliaan 2014). This accumulation continues up to the post-
mote self-aggression (Polsek et al. 2011). Other studies natal period, being dependent on breastmilk (Janssen and
pointed out that ASD behavior arises from a dysfunction in Kiliaan 2014).
the midbrain dopaminergic system (Paval 2017). In fact, the DHA can be obtained from diet or synthesized from
use of dopamine D2 receptor antagonists showed to be effi- a-linolenic acid (ALA, 18:3n-3), a n-3 PUFA found in wal-
cient in ameliorating autistic symptoms, and this could be nut, chia, flax seeds, rapeseed and soy. In the liver, ALA
due to the mediation of glutamate release via D2, confirm- undergoes a desaturation by D6-desaturase, an elongation,
ing the excitation/inhibition imbalance theory (Bernardi and another desaturation by D5-desaturase to finally form
et al. 2011). Eicosapentaenoic acid (EPA, 20:5n-3). EPA is elongated to
ADHD symptoms, on the other hand, arise from a deficit 22:5n-3 and 24:5n-3, which is again desaturated to 24:6n-3.
in executive function, including attention and inhibitory Finally, in peroxisome, 24:6n-3 is b-oxidized to DHA
control, and working memory (NIH 2016). These children (22:6n-3) (Domenichiello, Kitson, and Bazinet 2015). In
are also predisposed to present delays in language and humans, the ability to convert ALA to DHA is extremely
motor development, associated with impaired brain activity limited – less than 0.1% (Weiser, Butt, and Mohajeri 2016)
in several neuronal networks (NIH 2016). –, especially in the fetus, making them highly dependent on
Patients with ADHD seem to experience normal steps of the transfer of maternal DHA through the placenta. This is
cortical maturation but slower than healthy controls influenced by maternal DHA synthesis, mobilization from
(Dougherty et al. 2016). A volume reduction and a cortical adipose stores, and dietary intake (Lauritzen and Carlson
thinning in certain brain regions, mainly in frontal and pre- 2011). Furthermore, the desaturase enzymes are not only
frontal regions, was found in children with ADHD (Batty responsible for the conversion of ALA into DHA, but also
et al. 2010), but the most replicable abnormalities are in of Linoleic acid (LA, an n-6 PUFA) into Arachidonic acid
basal ganglia, being associated with the severity of the symp- (ARA), the second most important PUFA, next to DHA, for
toms (Nakao et al. 2011). brain growth (Morgese and Trabace 2016).
Dougherty et al. (2016), comparing the structural imaging DHA, EPA and ARA, also known as Long Chain (LC)-
of the ASD and ADHD brain, have found differences in PUFAs, modulate phospholipids composition, involved in
total brain volume, amygdala, and internal capsule. For this membrane fluidity, being able to control the functions of
last alteration, the results in ASD were unclear, while in enzymes, ion channels and receptors, and to regulate
1434 B. P. MARTINS ET AL.

neurotransmission (Morgese and Trabace 2016). They are (Steer et al. 2013). Some observational studies reported no
also important for dendritic growth and neuronal synapto- association between maternal fish consumption (Valent
genesis and can regulate inflammation (Cardoso, Afonso, et al. 2013), DHA in mothers’ red blood cell (RBC)
and Bandarra 2017). EPA and ARA are precursors of eicosa- (Bernard et al. 2013; Valent et al. 2013) and improvement in
noids (prostaglandins, thromboxanes and leukotrienes), but neurodevelopmental outcomes of healthy children. Note
while ARA shows proinflammatory properties, EPA exerts that although these studies were performed in healthy chil-
anti-inflammatory effects (Janssen and Kiliaan 2014). On the dren, these symptoms are also present in ASD and some
other hand, DHA cannot produce eicosanoid, but it is a in ADHD.
source of docosanoids, metabolites that can have the ability Regarding the randomized clinical trials (RCTs), Mulder,
to inactivate pro-inflammatory and pro-apoptotic signaling King, and Innis (2014) showed that infants in the placebo
(Cardoso, Afonso, and Bandarra 2017; Janssen and Kiliaan group had an increased risk of developing language prob-
2014). In addition to have a general pro-inflammatory effect, lems, an important symptom of ASD, than those whose
higher consumption of n-6 PUFAs increases the competition mothers received 400 mg/day of DHA during pregnancy.
between LA and ALA, as substrates of the enzymes stated Two other studies, with DHA supplementation alone,
above, resulting in a lower conversion of ALA to DHA and reported higher scores on autonomic and motor skills scales
a lower DHA levels in the mother and fetus (Janssen and at 14 days of age, when mothers were supplemented with
Kiliaan 2014). Low DHA levels could be harmful for neuro- 600 mg/day of DHA from 12 to 20 weeks’ gestation until
development, especially in preterm infants, who are deprived birth (Gustafson et al. 2013), and better problem solving
of maternal stores in the third trimester (Dunstan et al. in infants of mothers who received 214 mg/day of DHA in
2008; Hall 2016). Overall, an optimal DHA intake during same period (Judge, Harel, and Lammi-Keefe 2007). In
pregnancy and postnatal period appears essential, and global Gustafson’s study (2013), a more mature autonomic func-
recommendations for pregnant and lactating women to have tion indicates greater flexibility and integrity of the
a minimum DHA intake of 200 mg/day should be imple- Autonomic Nervous System, probably reflecting a better
mented (Global Organization for EPA and DHA omega- physiological reactivity of the newborn to the environment.
3s 2017). However, this study had a significantly low rate of comple-
The necessary amount of dietary DHA can be obtained tion (78%) and the majority of enrollees were non-White,
mainly through fish and other seafood intake. However, but African American, reporting higher pre-DHA status.
recent studies indicate that pregnant women do not have In DHA plus EPA prenatal supplementation’s group,
enough information about the importance of fish consump- other studies found interesting results (Campoy et al. 2011;
tion, since guidelines emphasizing the health risks of Dunstan et al. 2008; Escolano-Margarit et al. 2011; Gould,
methyl-mercury (MeHg) can make them doubtful and inse- Smithers, and Makrides 2013; Makrides et al. 2010;
cure (Starling et al. 2015). A large observational study Makrides et al. 2014; Meldrum et al. 2015). For example, in
showed that children whose mothers consumed lower sea- a study with high level of methodological rigor with
food (<340 g/week) during pregnancy had increased risk of low attrition, Makrides et al. (2010) studied preterm infants
having lower verbal IQ and lower fine motor ability, and whose mothers were supplemented with 800 mg DHA þ
suboptimum outcomes for social behavior, communication 100 mg EPA per day, from <21 weeks of gestation until
and social development at 6 months to 8 years of age, com- birth. These authors found that few children in the DHA
pared to children whose mothers consumed high seafood group had scores indicative of mildly delayed cognitive
diets (Hibbeln et al. 2007). Currently, although it is known development, supporting the evidence that DHA supplemen-
that MeHg is neurotoxic at high levels, the effect in neuro- tation is effective at preventing developmental delay in early
development of its exposure in low-level from fish intake childhood. However, they did not find differences between
remains controversial (Strain et al. 2015). This effect appears groups in any scales of the Behavior Rating Inventory of
to be influenced by n-6 to n-3 PUFA ratio, suggesting that Executive Function at 4 years of age (Makrides et al. 2014).
the balance of this ratio may reflect the capability of these Note that although this study was not a pure DHA test,
LC-PUFAs, at higher levels, to increase or protect, respect- since it used fish oil capsules containing both DHA and
ively, inflammation induced by MeHg (Strain et al. 2015). EPA, DHA is present in the brain at levels 50 and 200-fold
Furthermore, the benefits of fish consumption, probably due higher than EPA and ALA, respectively (Domenichiello,
to its high DHA composition, may overcome or mask the Kitson, and Bazinet 2015).
potential MeHg’s adverse effects on neurodevelopmental Tables S1 and S2 (Supplementary material) show the
outcomes (Gale et al. 2008; Mendez et al. 2009; Oken et al. results of observational and RCTs’ studies regarding the
2008a; Oken et al. 2008b; Strain et al. 2015). association between maternal DHA intake during pregnancy
Other authors reported that a high DHA status in umbil- and infant neurodevelopmental outcomes. Overall, RCTs
ical cord blood were associated with longer gestation, results from maternal supplementation still appear inconclu-
better visual acuity and higher levels of novelty preference at sive and some meta-analyses concluded that maternal n-3
6 months, and higher cognitive scores at 11 months PUFA supplementation (DHA or DHA þ EPA) had no con-
(Jacobson et al. 2008), better motor development and fewer sistent effect on children neurodevelopment (Gould,
internalizing behavior problems at 7 years (Krabbendam Smithers, and Makrides 2013; Newberry et al. 2016). Note
et al. 2007), and higher verbal and full-scale IQ at 8 years that the majority of these studies have important limitations,
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1435

particularly high attrition rates, small sample sizes, and However, even if all of breastmilk is consumed by the
poor statistical design. Moreover, although several authors baby, the DHA intake is only 13–26 mg/day (0.2–0.4% of
did not generally demonstrate a positive effect of maternal total fatty acids), clearly below the rate of uterine accretion
prenatal n-3 PUFA supplementation (Campoy et al. 2011; of 45–50 mg/kg/day (Lapillonne et al. 2013). This amount
Escolano-Margarit et al. 2011; Hurtado et al. 2015; Makrides appears to be sufficient for normal brain development in
et al. 2010; Makrides et al. 2014; Meldrum et al. 2015; full-term infants, as long as mother consumes optimal
Ramakrishnan et al. 2015; Van Goor et al. 2011), with few amounts of DHA during peri-natal period (Colombo et al.
showing a negative effect (Gould et al. 2016; Gould et al. 2011; Colombo et al. 2013; Drover et al. 2011; Willatts
2017), some found that children with better neurodevelop- et al. 2013).
ment outcomes individually had higher DHA levels Some clinical evidence proposed that supplementing both
(Campoy et al. 2011; Escolano-Margarit et al. 2011; DHA and ARA instead of DHA alone is critical to optimal
Makrides et al. 2010; Ostadrahimi et al. 2017; Van Goor influence on neuronal development of full-term infants
et al. 2011). Furthermore, two of these studies (Campoy (Birch et al. 2007; Drover et al. 2011; Willatts et al. 2013)
et al. 2011; Escolano-Margarit et al. 2011), gathering infor- (see Supplementary material, Table S3). For example, verbal
mation from 3 European countries with high seafood IQ and visual acuity at 4 years of age was comparable
intakes, found that 84.4% of the mothers at the start of sup- between infants receiving both 0.36% DHA and 0.72% ARA
plementation had already achieved the recommended DHA during the first 4 months of life and breastfed infants,
intake of 200 mg per day, and that, in this group, parental whereas verbal IQ was lower in infants receiving DHA alone
level of education was also relatively high (Escolano- (Birch et al. 2007). Moreover, Drover et al. (2011) showed
Margarit et al. 2011). These authors concluded that, possibly, that a DHA-standard concentration of 0.32% was adequate
the positive effects of DHA supplementation during prenatal to improve cognitive function while higher concentrations
period are less apparent in mothers who already have an (about 0.96% of total fatty acids) did not confer additional
optimal dietary DHA supply. The responsiveness to prenatal benefit and may also contribute to competing and lower
DHA could be related to the characteristics of the specific ARA levels. This could mean that there is possibly an upper
population groups studied, and DHA status could be a limit to the benefit of intaking DHA (Colombo et al. 2011;
proxy for socio-economic background and healthy life-style Colombo et al. 2013; Drover et al. 2011). Although these
factors, that may synergically improve brain development benefits may be due exclusively to ARA supplementation,
(Gould et al. 2016; Van Goor et al. 2011). no study to date has investigated the effects of ARA supple-
It is also important to maintain optimal DHA levels dur- mentation alone on cognitive development, while studies
ing postnatal period. At this time, breastmilk is the main with only DHA-enriched formula have already reported
source of DHA in infant
s RBC (Harslof et al. 2013), being positive effects of this supplementation (Gale et al. 2010).
dependent on maternal DHA consumption (Lauritzen and Other studies, however, did not find short- (Colombo et al.
Carlson 2011). 2013; Pivik et al. 2009) or long-term (de Jong et al. 2010;
DHA from breastmilk seems to be crucial for better lan- Willatts et al. 2013) benefits in some cognition measures
guage and cognitive function (Belfort et al. 2013; Quigley using LC-PUFA supplements.
et al. 2012; Whitehouse et al. 2011), social behavior with On the other hand, the standard amount of DHA may
fewer attentional symptoms, and better global psychosocial not be an adequate approach for preterm infants, who
health (Hayatbakhsh et al. 2012; Oddy et al. 2010). Oddy appear to be more sensitive to the effects of maternal
et al. (2010) showed that breastfeeding for less than DHA intake.
6 months was an independent predictor of mental health
problems, such as behavior problems, through childhood
The clinical example of preterm infants, a risk
and adolescence. In the cases of shorter duration of breast-
factor for ASD and ADHD
feeding, a maternal fish intake at least 2 fish times/week
could have a protective effect on neurodevelopment Preterm infants appear to have deficits in myelin integrity
(Mendez et al. 2009). However, other studies did not find and connectivity of the cortical circuits (Constable et al.
significant effects of breastfeeding on children’s neurodevel- 2008; Tam et al. 2016), presenting a higher risk for ASD
opment (Belfort et al. 2016; Bernard et al. 2017; Gale et al. and ADHD, mood, and psychotic disorders (McNamara,
2010; Girard, Doyle, and Tremblay 2017; Jacobson et al. Vannest, and Valentine 2015). Their lower DHA levels may
2008; Kramer et al. 2008; Lind et al. 2014) (see be partially responsible for this impaired neurodevelopment
Supplementary material, Table S1). This discrepancy in stud- (McNamara, Vannest, and Valentine 2015; Tam et al. 2016).
ies’ results could be due to level of control for potential con- Recent studies have shown that a short-term high DHA
founders such the heterogeneous composition of breast dose (0.86–1% of total PUFAs) seems to be helpful for an
milk, maternal IQ, education level, social economic status, optimal neurodevelopment in preterm infants (Henriksen
home environment and child care, and/or different methods et al. 2008; Makrides et al. 2009; Smithers et al. 2008),
of assessment of outcomes (Gale et al. 2010; Girard, Doyle, mostly in very low birth weight (VLBW) babies (<1500 g)
and Tremblay 2017). Women who were more intelligent or (Henriksen et al. 2008; Westerberg et al. 2011) (see
better educated seem to be more receptive to breastfeeding Supplementary material, Table S3). For example, Makrides
promotion (Gale et al. 2010). et al. (2009) found that a DHA supplementation of about
1436 B. P. MARTINS ET AL.

1% of total PUFAs, from day 2 to 4 until term-corrected unaffected children (Mazahery et al. 2017). Parletta,
age, reduced cognitive delay, improved the neurological Niyonsenga, and Duff (2016) showed that a worse PUFA
development of girls and was strongly indicative of profile, especially in relation to this PUFA ratio, is associ-
improved neurodevelopment in very preterm infants ated with clinical severity in children with ASD or ADHD.
(33 weeks gestation) at 18 months of age, compared to Additionally, a mechanistic model linking the ASD pheno-
those with a standard-DHA diet (0.3% of total fatty acids). type and DHA deficiency has been proposed recently,
In this study, ARA intake was the same in both groups (0. together with a testing strategy to verify this connection
6% of total fatty acids). Henriksen et al. (2008) found also (Hall 2016).
that a high-DHA supplementation (0.86% DHA plus 0.91% The low n-3 PUFA levels in ASD can be explained by
ARA) in VLBW infants, during nine weeks, led to better defects in enzymes involved in the DHA and EPA produc-
problem solving and recognition memory at 6 months of tion from ALA, known as fatty acid desaturase (FADS), by
age. This latter function is essential to focus attention, learn- deficiencies in its process of cell membrane incorporation,
ing and information processing. Lastly, Westerberg et al. or an alteration in its metabolism, for example through a
(2011) reported a better-sustained attention at 20 months of possible dysfunction in mitochondrial PUFA oxidation (Das
age in these high-DHA group but did not find differences in
2013; Van Elst et al. 2014). However, their potential bio-
mental and motor development scores between the groups.
logical pathways in ASD are not yet fully understood
However, their plasma DHA concentration was positively
(Das 2013).
correlated with Bayley Mental Developmental Index, show-
A deficit of DHA during perinatal period was shown to
ing that this nutrient may be one of the factors that influ-
be associated with a reduction in neurogenesis and delays in
ence the development of VLBW babies. Nevertheless, at
neuronal migration (McNamara et al. 2017), and it has
8 years of age, these children had no differences in brain
macrostructure (volume, area and thickness through imaging recently been implicated in synaptic plasticity (Delorme
data), behavioral outcome and cognitive functions (Almaas et al. 2013) – a new research field in ASD (Delorme et al.
et al. 2015). Other long-term studies did not report signifi- 2013; Ebert and Greenberg 2013). ASD is also characterized
cant benefits in infancy, including for executive functions, by changes in myelination and by an abnormal long-range
ADHD and ASD symptoms, and emotional or behavior brain connectivity. Additionally, the formation of white mat-
problems (Collins et al. 2015; Isaacs et al. 2011; Molloy et al. ter tract appears to be very susceptible to the n-6 to n-3
2016; Smithers et al. 2010). PUFA ratio (Durand et al. 2013). Moreover, a low maternal
Overall, some meta-analysis concluded that there is insuf- intake of DHA was associated with a decrease in brain-
ficient evidence to recommend DHA supplementation in derived neurotrophic factor (BDNF), a protein that protect
preterm (Schulzke, Patole, and Simmer 2011), and also in neurons and glia from death (Lukiw and Bazan 2008;
full-term infants (Koletzko et al. 2008; Qawasmi et al. 2012; Taurines et al. 2014). Children with ASD have lower BDNF
Simmer 2011), with respect to potential long term neurode- levels, associated with more severe disease (Taurines et al.
velopmental benefits. Nevertheless, it cannot be ignored that 2014), and a supplementation with DHA could normalize
the studies stated above showed that a high DHA dose in BDNF in some brain areas affected in ASD (Wu, Ying, and
preterm infants could reduce, in short-term, the typical Gomez-Pinilla 2011).
symptoms found in ASD and ADHD, diseases that are also From a neurochemical point of view, there are studies
characterized by lower levels of this nutrient. However, the that point to the effect of DHA deficiency on the modula-
differential effect of this nutrient on healthy versus ASD/ tion of GABA-ergic receptor functions, especially in specific
ADHD states is one of the most important issues to be GABAA receptor subunits (Hamazaki and Hamazaki 2008),
addressed (Parellada et al. 2017). or to an interaction between PUFAs and PLA2
(Phospholipase A2), present in the plasma membrane (Van
How can DHA be related to ASD and ADHD? Elst et al. 2014). PLA2 is able to inhibit GABAA receptor
function and high n-6 ARA levels may increase its activa-
Potential mechanistic pathways of DHA in ASD tion, resulting in increased neuronal excitability (Van Elst
Women appear to have a higher conversion rate of ALA et al. 2014). In addition, a lower n-3 PUFA intake in rats
into DHA, associated with higher hepatic expression of has shown to reduce dopamine levels in frontal cortex,
PUFA desaturase enzymes, and probably longer DHA half- increase basal synaptic release of serotonin and change glu-
life in the plasma compared to men (Domenichiello, Kitson, tamatergic system in offspring female rats (Kodas et al.
and Bazinet 2015). This could indicate that DHA have an 2004; Moreira et al. 2010; Zimmer et al. 1998). Then, a
important role in ASD since it is more frequent in boys DHA supplementation increased synaptic plasticity in hip-
(Hall 2016; Morgese and Trabace 2016). The higher conver- pocampal neurons and improved glutamatergic neurotrans-
sion capacity in females may be due to the importance of mission (Kim, Spector, and Xiong 2011). However,
maintaining optimal DHA levels for their offspring’s devel- following its supplementation, DHA levels increase differ-
opment during pre- and postnatal period (Cardoso, Afonso, ently in the various brain regions (Van Elst et al. 2014). As
and Bandarra 2017). Actually, several studies reported that the hippocampus and frontal cortex are the brain regions
children with ASD have lower DHA, EPA and ARA levels that take the longest time to recover normal DHA levels
and higher total n-6 to n-3 PUFA ratio compared to after its prenatal deficit, it may be difficult to restore its
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1437

concentration in the absence of a postnatal dietary interven- 2009), plasma levels only reflect its intake in the last days
tion (Pardo and Eberhart 2007). (Chang et al. 2018).
Regarding the problem of systemic immune dysfunction Several authors suggested that, as a deficient fetal DHA
present in up to 60% of autistic patients (Pardo and level results in deficits in white matter integrity and in a
Eberhart 2007), Weiser, Butt, and Mohajeri (2016) showed reduction of functional connectivity in fronto-basal glial cir-
that a high maternal dietary DHA in mouse protect off- cuits (found in preterm infants), it could increase the risk of
spring from the deleterious effects of maternal infection on developing ADHD symptoms in childhood (McNamara
ASD behavior symptoms, and later on immune system et al. 2017).
reactivity in adulthood. Furthermore, neuro-inflammation in The most studied mechanism relating DHA intake to the
the autistic brain has been reported several times (Careaga, pathophysiology of ADHD is the alteration in cortical dopa-
Van de Water, and Ashwood 2010; Madore et al. 2016; mine neurotransmission (Cardoso, Afonso, and Bandarra
Onore et al. 2013), and the increase in the n-6 to n-3 PUFA 2017; Morgese and Trabace 2016). Dopamine levels and its
ratio is one of the possible reasons for this (Van Elst et al. binding to D2 receptors could be reduced, mainly in frontal
2014). In addition to its pro-inflammatory action, n-6 PUFA cortex, in chronic n-3 PUFA deficiencies, associated with
derived prostaglandins may be associated with initiation of symptoms similar to those observed in ADHD (Zimmer
preterm labor, with an increased risk of ASD in susceptible et al. 2002).
children (Van Elst et al. 2014). Mostafa, El-Khashab, and Other authors have also found a pro-inflammatory status
Al-Ayadhi (2015) found also higher serum levels of brain- in ADHD, supporting the idea that n-3 PUFAs present ben-
specific autoantibodies, namely anti-myelin basic protein, in efits in controlling ADHD symptoms by its anti-inflamma-
autistic patients, probably linked to a lower plasma DHA tory action. For example, Hariri et al. (2012) showed that
and higher n-6 to n-3 PUFA ratio. 8 weeks of EPA plus DHA supplementation decreased
Finally, the gut:brain axis was recently pointed as an plasma inflammatory mediators (C-reactive protein and IL-
alternative pathway for the n-3 PUFA action against ASD 6) and oxidative stress in children with ADHD, although its
(Madore et al. 2016). N-3 PUFA deficiency during perinatal impact on ADHD symptoms was not evaluated.
period alters intestinal microbial balance in offspring, induc- Overall, there is relatively little research regarding the
ing dysbiosis, with a reduction in bacterial density and a mechanisms of DHA in ADHD, compared to ASD informa-
decrease in the proportion of Firmicutes to Bacteroidetes tion. Recently, the gut:brain axis was also reported to influ-
(Gibson et al. 2015; Madore et al. 2016). N-3 PUFA supple- ence ADHD symptoms and diagnosis (Gould et al. 2017).
mentation showed to promote an increase in gut Indeed, it should be noted that low DHA intake has been
Lactobacillus and Bifidobacterium species and a decrease in associated with anxiety disorders (Liu et al. 2013), a risk fac-
potential pathobionts, such as in Enterobacteriaceae family tor for ASD and ADHD, while its supplementation has
(Madore et al. 2016). On the other hand, microbial over- shown anxiolytic effects (Jacka et al. 2012). Therefore, an
growth can affect the uptake and metabolism of PUFAs and adequate DHA intake during pregnancy may lead to benefi-
other molecules (Madore et al. 2016). As this axis is differ- cial effects in children with ADHD or ASD also by reducing
ent among people, its variation in ASD patients may be one anxiety symptoms in their mothers.
of the explanations for the inconsistent results in n-3 PUFA
supplementation studies. The role of maternal intake of DHA in the
Overall, the majority of these studies underscore the prevalence and risk of ASD and ADHD
important role of n-3 PUFAs, especially DHA, with an opti-
mal n-6 to n-3 PUFA ratio of about 1-2:1, in the prevention The importance in ASD
or symptomatic improvement of ASD, recently indicating Several authors showed the importance of optimal DHA lev-
the gut:brain axis as a potential target for intervention els in healthy children in neurological and motor develop-
in ASD. ment, verbal IQ, social behavior, inattention and
hyperactivity, all damaged in ASD. However, how maternal
Potential mechanistic pathways of DHA in ADHD intake of DHA additionally affects the development of ASD
is less clear, and research dedicated to this topic is scarce
The study of Stevens et al. (1995) was the first to show a (see Supplementary material, Table S4). Recently, Julvez
link between ADHD and n-3 PUFAs. These authors found et al. (2016) reported that maternal seafood intake during
lower DHA and EPA plasma levels in ADHD children, with pregnancy, particularly fish with a high fat content, confers
an overlap of PUFA deficiency and ADHD symptoms: thirst, some protection against autism spectrum characteristics in
frequent urination, dry skin and hair and nail weakness. offspring at 5 years of age, with a moderate attenuation after
Recently, a meta-analysis (Chang et al. 2018) showed that adjustment for LC-PUFA (including DHA) levels in cord
youth with ADHD have lower RBCs DHA, EPA and total blood. Associations remained positive above the previously
n-3 PUFAs but not lower levels of total n-6 PUFAs. recommended level of 340 g/week of fish during pregnancy,
However, no differences were reported in PUFA plasma lev- which appear to confirm the importance of optimal mater-
els compared to controls, showing that while RBCs PUFAs nal DHA levels in preventing or ameliorating ASD symp-
are strongly correlated with dietary intake of the previous toms in their children. Notably, in this study, cord-blood
month (Sun et al. 2007), and their brain levels (Pivik et al. mercury acted as an important biomarker of seafood intake
1438 B. P. MARTINS ET AL.

rather than having a neurotoxic association. Lyall et al. neurodevelopment; other potential molecules, such as oxyto-
(2013) also showed that women with the lowest total n-3 cin and serum insulin-like growth factor (IGF), are
PUFA intake (the lowest 5% of the distribution) had a 53% increased in breastmilk and could influence the risk of ASD
increase in risk of having a child with ASD as compared (Tseng et al. 2017). These findings may be useful for mater-
with women in the highest 90% of the distribution. nal counseling, especially in cases of risk of having ASD.
However, these authors did not find this association when Other studies further indicated that more than a deficit
DHA levels were assessed specifically. Indeed, no significant of DHA intake, a higher maternal n-6 to n-3 PUFA ratio
associations were found between n-3 PUFA intake in the during pregnancy was associated not only with worse neuro-
upper quartiles, or maternal fish intake, and ASD risk, sug- developmental outcomes (Bernard et al. 2013; Valent et al.
gesting that once the minimum requirements of total n-3 2013) but also with higher number of autism traits in off-
PUFA intake for normal development are met, a higher spring (Graaff et al. 2016). Graaff et al. (2016) pointed out
intake may provide little or no benefit. Note that a major that these associations were independent of child intelli-
bias in this study relies on the fact that ASD diagnoses were gence, suggesting that the PUFAs distribution specifically
not performed by a clinical evaluation and, therefore, the affects the development of autistic traits in addition to gen-
results should be interpreted with caution. Also, since eral neurodevelopment. On the other hand, maternal n-3
maternal fish consumption had no significant impact on PUFA status and prenatal intake of fish were not associated
ASD risk, other dietary sources of n-3 PUFA may have con- with child autistic traits. These findings suggest that, pos-
tributed to the results. In fact, the relation between maternal sibly, the focus of dietary interventions should not be only
consumption of fish, the main source of DHA and EPA, the increasing of n-3 PUFA intake but also the reduction of
and the risk of ASD remain controversial, with other studies food intake with high content of n-6 PUFAs.
reporting no association between them (Graaff et al. 2016).
However, Gao et al. (2016) and Julvez et al. (2016) found a
The importance in ADHD
protective effect of fish intake during or before pregnancy
against ASD diagnosis, respectively. Note that in all of these As in ASD, it was proposed that maternal DHA intake dur-
studies, the information associated with the type of fish con- ing pregnancy and lactation influences the neurodevelop-
sumed and the culinary process is missing. ment of susceptible children to ADHD (Morgese and
DHA requirement during pregnancy has to be combined Trabace 2016) (see Supplementary material, Table S5).
with an optimal postnatal and early childhood dietary intake Some studies reported that higher maternal DHA levels
of it, important for cortical circuits’ maturation (Van Elst at birth were associated with lower ADHD symptoms, such
et al. 2014). If it does not happen, it appears to become a as inattention in toddlers (Kannass, Colombo, and Carlson
risk factor that acts synergistically with other factors in the 2009) and hyperactivity/inattention during school age
promotion of the pathogenesis of ASD among susceptible (Kohlboeck et al. 2011). Gale et al. (2008) also showed that
children (Al-Farsi et al. 2013). children whose mothers had eaten fatty fish, rich in EPA
Few studies have investigated the potential protective and DHA, early in pregnancy had a lower risk of hyper-
effects of breastfeeding against behavioral problems such as activity compared to those whose mothers did not eat fatty
ADHD symptoms, and even fewer on ASD traits. Studies in fish. In addition, Sagiv et al. (2012) found a protective asso-
this area found mixed results: while some showed a positive ciation of ingestion of more than 2 times/week of fish with
association between breastfeeding and ASD (Al-Farsi et al. ADHD-related behaviors, particularly DSM-IV Impulsive/
2012; Boucher et al. 2017; Julvez et al. 2007; Schultz et al. Hyperactive behaviors. However, other studies did not detect
2006; Shafai et al. 2014), others did not (Husk and Keim any benefits of prenatal seafood intake in attention, once
2015). For example, Al-Farsi et al. (2012) found that, in confounders were taken into consideration (Hibbeln et al.
ASD, there are more suboptimal breastfeeding practices 2007). Once again, in ADHD studies, no author has
comparing to the control group. In agreement, a recent included information regarding seafood intake as doses and
meta-analysis provides evidence that breastfeeding may pro- culinary treatment.
tect against ASD (Tseng et al. 2017). Boucher et al. (2017) Regarding supplementation studies, there are also mixed
reported that each additional month (>6 months) of breast- results: while some authors reported a beneficial effect of
feeding was associated with a small improvement in cogni- prenatal DHA supplementation on measures of attention
tive function and with slightly fewer autistic traits, and more and executive function at preschool age (Jensen et al. 2010;
mitigated effects were found on ADHD symptoms and Ramakrishnan et al. 2016), others did not find any associ-
attention function. However, these authors did not find sig- ation (Gould et al. 2014). Although these studies addressed
nificant association between breastfeeding duration and the healthy population, Ramakrishnan et al. (2016) showed that
occurrence of scores within the clinical range for ASD and the same results were present in children with ADHD.
ADHD diseases. Finally, Schultz et al. (2006) found that the Breastfeeding is one of the factors that could be related
use of infant formula without DHA plus ARA supplementa- to ADHD and the prevalence of ADHD among patients not
tion versus exclusive breastfeeding was associated with a sig- fed with breastmilk, but with artificial formula, is signifi-
nificant increase in the odds of autistic disorder. cantly higher compared to those who are fed with breast-
Nevertheless, DHA is only one of the factors that contribute milk (Groen-Blokhuis et al. 2013; Mimouni-Bloch et al.
to the beneficial effects of breastmilk in childhood 2013; Park et al. 2014; Stadler et al. 2016). Moreover,
 CRITICAL REVIEWS IN FOOD SCIENCE AND NUTRITION 1439

breastmilk seems to prevent ADHD, once breastfeeding of their offspring, resulting in lower cognitive and language
shorter duration appears to be associated with an increased function, motor ability, poorer social and communication
internalizing, externalizing, and overall behavioral problems skills, and behavior problems. However, RTCs and other
as well as the diagnosis of ADHD (Mimouni-Bloch et al. controlled studies have not shown the same consistent posi-
2013; Park et al. 2014; Stadler et al. 2016). tive results as found in observational studies. Indeed,
In summary, the present review included 73 studies, although the results from maternal supplementation RCTs
reported in Supplementary material, Tables S1–S5. Of these, still appear inconclusive, some studies pointed that DHA
59 studies reported the effect of DHA on various neurodeve- status in cord and maternal blood are associated with better
lopmental outcomes in the offspring and only 9 and 5 studies childhood neurodevelopmental outcomes. One possible
concerned individuals with ASD and ADHD, respectively. explanation for this is that, during pregnancy, DHA is not
Of the 9 ASD studies, DHA was measured in biological the unique factor to intervene in this development, as other
samples in 2 cases. Three categories were used to summarize factors such as birth weight, maternal education, maternal
the conclusions (Supplementary material, Table S4): IQ, and smoking may mask the benefits of this intervention.
“positive association”, when there was a statistically signifi- In addition, the baseline DHA intake/status is not systemat-
cant positive association with the clinical diagnosis of ASD ically included in the characterization of the population
(n ¼ 5); “inconsistent association”, when a positive associ- study. As this status could affect the response to changes in
ation was detected with autism traits but no clinical diagno- DHA intake, this may also be one of the reasons for the
sis was established (n ¼ 2); and “no association”, when no lack of significant association found in these studies.
statistically significant association was found between the Besides DHA deficits in prenatal period, an optimal
two variables (n ¼ 2). DHA intake during the postnatal period may represent a
In the 5 ADHD studies (Supplementary material, Table safe and efficacious strategy to mitigate these deficits.
S5) DHA was not measured. All of 5 studies reported a posi- Breastfeeding is a natural and efficient DHA source.
tive association between breastfeeding and ADHD diagnostic. However, DHA content of human milk is highly variable, it
In the 59 studies addressing the normal neurodevelop- depends on mother’s diet and her FADS genetic make-up
mental (Supplementary material, Tables S1–S3): in the (Brenna et al. 2007; Fidler et al. 2000; Hall 2016; Xie and
observational studies (n ¼ 24) DHA was measured in bio- Innis 2008). Preterm infants need higher DHA levels than
logical samples in 9 cases. Thirteen showed a “positive full-term infants. They seem to have a higher risk for ASD
association”, 4 showed “inconsistent association”, 6 showed and ADHD, and a high dose of DHA could reduce the typ-
“no association” and 1 showed “conflicting results”; in the ical symptoms found in ASD and ADHD at short-term but
prenatal RCTs studies (n ¼ 17), 2 showed a “positive not in long-term. Additionally, in this period, it seems to be
association”, 5 showed “inconsistent association”, 9 showed more important to have an optimal n-6 to n-3 PUFA ratio
“no association” and 1 showed “conflicting results”; in the than ideal levels of DHA. Although these results were found
postnatal RCTs studies in full-term infants (n ¼ 9), 1 showed in healthy children, collectively, these findings may provide
a “positive association”, 4 showed “inconsistent association” support for the proposition that reduced perinatal DHA
and 4 showed “no association”; in the postnatal RCTs stud- accrual in brain may represent a risk factor for ASD
ies in preterm infants (n ¼ 9), 1 showed a “positive and ADHD.
association”, 3 showed “inconsistent association” and 5 Recent studies in ASD found that an optimal maternal
showed “no association”.” consumption of fish and breastfeed for 6 months or more,
could confer some protection against autism spectrum char-
acteristics in offspring, while a higher maternal n-6 to n-3
Discussion
PUFA ratio seems to be associated with higher autism traits
ASD and ADHD arise from interactions between genetic in offspring. In addition, the brain-microbiota axis is a
and environmental factors that influence neurobiological future tool for finding more effective strategies to prevent or
systems beginning in the prenatal period. It is unlikely that treat ASD, and probably ADHD. These results were similar
a single neuroanatomical or neurophysiological change is for ADHD, also showing positive findings of maternal DHA
responsible for all the pathogenesis of ASD and ADHD. An intake in the reduction of ADHD symptoms, although other
alteration in brain volume is one of the more consistent fea- studies did not demonstrate this association.
tures of ASD and ADHD, but other problems, such as in In conclusion, DHA and EPA-rich food, particularly in
myelin integrity, connectivity of the cortical circuits, neuro- pre- and postnatal period, appear to have a positive impact
transmission and neuroinflammation, were also described. in some populations of offspring. Particularly in very pre-
N-3 PUFAs, especially DHA, are necessary for neurode- term infants and very low birth weight infants, research has
velopment. Their tissue concentrations in fetal plasma and shown the role of DHA in neurodevelopmental outcomes
brain are dependent on maternal diet intake, mainly through and the importance of having an optimal n-6 to n-3 PUFA
fatty fish and other seafood consumption. This intake is par- ratio. Early deficits of DHA in fetal brain may possibly
ticularly important during the third trimester of pregnancy impinge normal development and represent a modifiable
until the first six months of life. In fact, the current review risk factor for ASD and ADHD. In order to clarify this role,
shows that a low maternal intake of fish (or low DHA lev- more and better-quality studies, especially focused on ASD
els) during pregnancy can affect the neurodevelopment of and ADHD diagnosed populations, are necessary. It is also
1440 B. P. MARTINS ET AL.

important to include the individual baseline intake/status of control study. Nutrition 28 (7–8):e27–32. doi:10.1016/
DHA to predict who will benefit from an intervention j.nut.2012.01.007.
Al-Farsi, Y. M., M. I. Waly, R. C. Deth, M. M. Al-Sharbati, M. Al-
through diet supplementation or optimization. Recently, the
Shafaee, O. Al-Farsi, M. M. Al-Khaduri, S. Al-Adawi, N. W.
Food and Drug Administration (FDA) and the Hodgson, and I. Gupta. 2013. Impact of nutrition on serum levels of
Environmental Protection Agency, recommend that preg- docosahexaenoic acid among Omani children with autism. Nutrition
nant women, women who might become pregnant, and 29 (9):1142–6. doi:10.1016/j.nut.2013.03.009.
breastfeeding mothers eat 2–3 servings of lower-mercury Almaas, A. N., C. K. Tamnes, B. Nakstad, C. Henriksen, K. B.
Walhovd, A. M. Fjell, P. Due-Tonnessen, C. A. Drevon, and P. O.
fish or 8–12 ounces (227–340 g) per week, while avoiding
Iversen. 2015. Long-chain polyunsaturated fatty acids and cognition
fish intake that is high in mercury (FDA 2017; EPA 2017). in VLBW infants at 8 years: an RCT. Pediatrics 135 (6):972–80. doi:
The novelty comparing to the recommendations of 2014 10.1542/peds.2014-4094.
was a creation of three categories of fish: (1) “Best choices” American Psychiatric Association (APA). 2013. Diagnostic and statis-
(eat 2–3 times/week; e.g. salmon (Costa et al. 2015), sardine tical manual of mental disorders. 5th ed. Arlington: American
Psychiatric Publishing.
(Bandarra et al. 2004), mackerel, horse mackerel, tilapia), (2)
Bandarra, N. M., P. Palma, I. Batista, M. L. Nunes, P. Branco, M.
“Good choices” (eat 1 time/week; e.g. hake, meager (Afonso Bruges, J. Dickson, B. Silva-Lima, G. Morais, J. D. Barata, et al.
et al. 2015; Costa et al. 2013), halibut, mahi-mahi, snapper) 2004. Supplementation of the diet of haemodialysis patients with
and (3) “Fish to avoid”; e.g. swordfish, tilefish, blue shark Portuguese canned sardines and evaluation of x3 fatty acid level in
(Matos et al. 2015). On the other hand, DHA supplementa- erythrocyte phospholipids. Journal of Aquatic Food Product
tion could be an alternative to optimize maternal DHA lev- Technology 13 (3):61–8. doi:10.1300/J030v13n03_06.
Baron-Cohen, S., and M. K. Belmonte. 2005. Autism: A window
els in women who do not achieve optimal level of fish onto the development of the social and the analytic brain.
intake, such as poorly nourished mothers, those on vegan Annual Review of Neuroscience 28 (1):109–26. doi:10.1146/
diets or those with a family history of mental illness. annurev.neuro.27.070203.144137.
Moreover, n-3 PUFAs supplements and fortified formulas Basson, M. A., and R. J. Wingate. 2013. Congenital hypoplasia of the
seem to be well tolerated. Newberry et al. (2016), in a recent cerebellum: developmental causes and behavioral consequences.
Frontiers in Neuroanatomy 7:29. [Database] doi:10.3389/fnana.
systematic review including 21 RCTs studies, found that the 2013.00029.
adverse effects of these supplementation in pregnant and Batty, M. J., E. B. Liddle, A. Pitiot, R. Toro, M. J. Groom, G. Scerif, M.
lactating women were limited to mild gastrointestinal (GI) Liotti, P. F. Liddle, T. Paus, C. Hollis. 2010. Cortical gray matter in
symptoms, with no serious adverse events reported. In attention-deficit/hyperactivity disorder: A structural magnetic reson-
infants, adverse events were also limited to GI symptoms, ance imaging study. Journal of the American Academy of Child and
Adolescent Psychiatry 49 (3):229–38. doi:10.1097/00004583-
with most serious adverse events related to morbidities asso- 201003000-00006.
ciated with prematurity. Belfort, M. B., S. L. Rifas-Shiman, K. P. Kleinman, D. C. Bellinger,
In summary, our results point to the need of more meth- M. H. Harris, E. M. Taveras, M. W. Gillman, and E. Oken. 2016.
odological sound research particularly addressing clinically Infant breastfeeding duration and mid-childhood executive function,
diagnosed ASD and ADHD populations to convey more behavior, and social-emotional development. Journal of
Developmental and Behavioral Pediatrics 37 (1):43–52. doi:10.1097/
robust conclusions and inform good practice.
DBP.0000000000000237.
Belfort, M. B., S. L. Rifas-Shiman, K. P. Kleinman, L. B. Guthrie, D. C.
Bellinger, E. M. Taveras, M. W. Gillman, and E. Oken. 2013. Infant
Disclosure statement feeding and childhood cognition at ages 3 and 7 years: Effects of
The authors declare no conflict of interest. breastfeeding duration and exclusivity. JAMA Pediatrics 167 (9):
836–44. doi:10.1001/jamapediatrics.2013.455.
Bernard, J. Y., M. Armand, H. Peyre, C. Garcia, A. Forhan, M. De
ORCID Agostini, M.-A. Charles, and B. Heude. 2017. Breastfeeding, polyun-
saturated fatty acid levels in colostrum and child intelligence quo-
Narcisa M. Bandarra http://orcid.org/0000-0002-7563-9226 tient at age 5-6 years. The Journal of Pediatrics 183:43–50.e3. doi:
Margarida Figueiredo-Braga http://orcid.org/0000-0003-2374-4371 10.1016/j.jpeds.2016.12.039.
Bernard, J. Y., M. De Agostini, A. Forhan, B. de Lauzon-Guillain,
M. A. Charles, and B. Heude. 2013. The dietary n6:n3 fatty acid
ratio during pregnancy is inversely associated with child neurodevel-
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