How the placenta-brain lipid axis impacts the nutritional origin of child neurodevelopmental disorders: Focus on attention deficit hyperactivity disorder and autism spectrum disorder

Abstract

Dietary fish is a rich source of omega-3 (n-3) fatty acids, and as such, is believed to have played an important role in the evolution of the human brain and its advanced cognitive function. The long chain polyunsaturated fatty acids, particularly the n-3 docosahexanoic acid (DHA), are critical for proper neurological development and function. Both low plasma DHA and obesity in pregnancy are associated with neurodevelopmental disorders such as attention deficit and hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) in childhood, and n-3 supplementation has been shown to improve symptoms, as reviewed herein. The mechanisms underlying the connection between maternal obesity, n-3 fatty acid levels and offspring’s neurological outcomes are poorly understood, but we review the evidence for a mediating role of the placenta in this relationship. Despite promising data that n-3 fatty acid supplementation mitigates the effect of maternal obesity on placental lipid metabolism, few clinical trials or animal studies have considered the neurological outcomes of offspring of mothers with obesity supplemented with n-3 FA in pregnancy.

1. Introduction

Did eating fish make us human? Homo Sapiens’ high brain to body weight ratio may have evolved due to their adoption of fish and shellfish in their diet (Crawford et al., 1999). Aquatic foods are high in the omega-3 (n-3) long chain polyunsaturated fatty acids (LCPUFA), such as docosahexanoic acid (DHA; 22:6, n-3) which in turn composes a high percentage of human neurological membranes. In fact, DHA is thought to be essential to brain growth, and cannot be replaced by other n-3 LCPUFA with fewer double bonds, such as docosapentanoic acid (DPA; 22:5), or eicosapentanoic acid (EPA; 20:5) (Crawford et al., 1999). Some researchers have argued that the largely pescatarian diet (aquatic foods and plants) of early H. Sapiens living on African lakeshores, also increased the levels of the n-6 LCPUFA, arachidonic acid (AA; 20:4) which is critical for vascular development, and abundant in highly vascular structures such as the placenta (Leonard et al., 2010). Placental lipid transport is particularly robust in humans, and human fetuses have the highest adiposity at birth of any mammal. Cunnane et al. argue eloquently that this high fat mass in human babies was key to the evolution of the large human brain (Cunnane and Crawford, 2003). Though evidence of particular dietary patterns of early humans must be interpreted with a high degree of uncertainty, potentially, early pescatarian diets rich in the LCPUFA and easily accessed by pregnant women, increased supply of brain building LCPUFA, placental growth, and thus fetal LCPUFA delivery and adiposity, which made rapid post-partum neurological development possible. Consistent with this, a recent systematic review concluded that fish consumption during pregnancy was beneficially associated with offspring neurocognitive outcomes (Hibbeln et al., 2019). Within, we will review the importance of n-3 LCPUFA to fetal brain development and the role of the placenta in the delivery of these essential fatty acids in utero. Additionally, we will discuss neurological consequences to insufficient dietary intake or placental delivery of these essential fatty acids, clinical trials aiming to treat children with those conditions with n-3 LCPUFA supplementation, and the evidence for n-3 LCPUFA supplementation in complicated pregnancies.

1.1. Search strategy

The following narrative review is intended to broadly discuss evidence for a placenta-fetal brain lipid axis in the context of fetal n-3 FA supply. Though not intended as a systematic review of such a large topic, we specifically employed pre-defined search criteria for our discussion of evidence of impact of n-3 FA supplementation on neurodevelopmental outcomes in children with ADHD and ASD. A literature search in PubMed identified articles from January 2007 to June 2021 describing treatment outcome of n-3 FA in children with ADHD and ASD. The search terms for ADHD and ASD included “attention deficit hyperactivity disorder (ADHD)” OR “attention” OR “hyperactivity” OR “autism spectrum disorder (ASD)” OR “autism”. The search terms for the treatment outcome included “omega 3 fatty acid” OR “fatty acid” OR “fish oil” AND “clinical trial” OR “trial”. We included all retrospective and prospective studies reporting symptomatic outcomes after n-3 FA treatment in the cohort of ADHD or ASD regardless of the diagnostic criteria, types of n-3 FA, or outcome measures used in the study, which may vary (see Table 1). We excluded studies without a placebo group or clear description of outcome measures. We extracted information of the year of publication, study location, outcome measures, treatment period, group size, participant sex, age of both treatment and placebo groups, and main results.

Table 1.

Clinical trials of LCPUFA supplementation to improve symptoms of ADHD and ASD.

DX	Reference and setting	Outcome measures	Treatment period	Treatment group				Placebo group				Main results
				N	Treatment (daily)	Age (SD) years	Sex (Male %)	N	Placebo (daily)	Age (SD) Years	Sex Male %
ADHD	Milte et al., 2012 Adelaide, Australia	Attention, cognition, literacy, and Conners’ Parent Rating Scales (CPRS), erythrocyte fatty acids,	12 mo	EPA 30 DHA 28	Randomized, controlled, three-way crossover trial. EPA-rich fish oil (1109 mg EPA and 108 mg DHA); DHA-rich fish oil (264 mg EPA and 1032 mg DHA)	8.77 (1.76) 8.89 (1.60)	80%M 75%M	29	Safflower oil 1467 mg LA	9.14 (2.03)	83%M	Increased erythrocyte EPA + DHA with improved word reading and lower oppositional behavior. Sub-group with learning disorder improved spelling and attention and oppositional behavior, hyperactivity, and cognitive problems.
	Perera et al., 2012 Colombo, Sri Lanka	11-item checklist assessed symptoms of ADHD and associated behavioral problems and learning difficulties	6 mos	48	Fish oil and cold-pressed evening primrose oil in the ratio 1.6:1, o3 592.74 mg, o6 361.5 mg	9.4 (1.5)	71%M	46	Sunflower oil	9.2 (1.5)	76%M	Improved restlessness, aggressive-ness, completing work, and academic performance. No effect in full sample. Sub-group with poor reading improved reading.
	Richardson et al. 2012 Oxford, UK	British Ability Scales (BAS II), Conners’ Rating Scales (CTRS-L and CPRS-L)	16 wks	180	Algal oil 600 mg DHA	8.69 (0.84)	53%M	182	Corrn/soybean oil 1500 mg	8.64 (0.83)	53%M	No effect in full sample. Sub-group with poor reading improved reading. Improved parent-rated behavior problems. No effects in either teacher-rated behavior or working memory.
	Widenhorn-Muller et al., 2014 Ulm, Germany	FBB ADHD parent-rated and teacher-rated questionnaires, Child Behavior Checklist (CBCL), eacher’s Report Formeacher’s Report Form, Hamburg Wechsler Intelligence Scales for Children–IV	16 wks	46	600 mg EPA, 120 mg DHA	8.90 (1.48)	76%M	19	Two olive oil-containing capsules	8.91 (1.35)	79%M	Improved working memory. No effect on other cognitive measures and parent- and teacher-rated behavior.
	Bos et al., 2015 Utrecht, Netherland	CBCL and Strengths and Weaknesses of ADHD symptoms and Normal behavior scale (SWAN), cheek cell, fMRI	16 wks	40 (ADHD 20, TD 20)	10 g of margarine daily, enriched with 650 mg EPA, 650 mg DHA	All 2 groups: ADHD 10.3 (2.0) TD 10.9 (2.0)	100%M	(ADHD 20, TD 19)	Placebo x16 wks	(no group based data)	100%M	Improved parent-rated attention in both children with ADHD and TD children. No effect of EPA/DHA supplementation on cognitive control or on fMRI measures of brain activity.
	Matsudaira et al., 2015 London, UK	Conners’ Teacher Rating Scales (CTRS-L), Conners’ Parents Rating Scales CPRS-L	12 wks	38	558 mg EPA, 174 mg DHA, 60 mg gamma-linolenic acid	13.7 (1.1)	100%M	38	Placebo: 6 capsules MCT oil/daily, for 12 weeks	13.7 (1.2)	100%M	No effect in CTRS, CPRS ADHD indices.
ASD	Barragan et al., 2017 Mexico City, Mexico	Spanish version of the ADHD Rating Scale (DuPaul, Power, Anastopoulos, & Reid, 1998), rated by the parents, and the Clinical Global Impressions–Severity (CGI—S) scale.	12 mos	Omega-3/6 30 Omega-3/6 + Methylphenidate 30	558 mg EPA, 174 mg DHA, and 60 mg gamma-linolenic acid +/− Methylphenidate	All 3 groups: 8.27 (1.74)	All 3 groups: 67%M	30	Methylphenidate	(no group based data)	(no group based data)	Improved ADHD symptoms in all groups. Omega-3/6 + MPH better than Omega-3/6 alone for ADHD Total and Hyperactivity-Impulsivity subscales. Less adverse events were in Omega-3/6 or MPH + Omega-3/6 than MPH alone.
	Cornu et al. 2018 multicenters, France	Attention-Deficit Hyperactivity Disorder Rating Scale version 4 (ADHD-RS-IV) 2ndary: lexical level (Alouette test), attention (Test of Attentional Performance for Children-KiTAP), anxiety (48-item Conners Parent Rating Scale-Revised-CPRS-R), and depression (Children’s Depression Inventory-CDI).	3 mos	80	Aged 6–8 years, EPA 336 mg and DHA 84 mg; aged 9–11 years, EPA 504 mg and DHA 126 mg; aged 12–15 years EPA 672 mg and DHA 168 mg	10.2 (2.8)	76%M	82	Olive oil	9.7 (2.5)	80%M	No improvement. Placebo group had greater reduction in total ADHD-RS-IV score than the DHA-EPA group. No effect in the other components of the Conners score.
	Dopfner et al., 2021 Cologne and Manheim, Germany	ADHD Parent and Teacher Rating Scale for Preschool Children (FBB-ADHS-V; Child Behavior Checklist 11/2 to 5 (CBCL 11/2–5), German version of the Kaufman Assessment Battery for Chil- dren (K-ABC).	4 mos	20	372 mg EPA, 116 mg DHA, and 40 mg gamma-linolenic acid	5.55 (0.61)	70%M	20	Empty capsules	4.97 90.93)	80%M	Improved parent- and teacher-rated ADHD symptoms, parent-rated internalizing symptoms, and parent- and teacher-rated externalizing symptoms
	Prenatal Intervention: Ramakrishnan et al. 2016 Cuernavaca, Mexico	McCarthy Scales of Children’s Abilities (MSCA), the parental scale of the Behavioral Assessment System for Children, Second Edition (BASC-2), and the Conners’ Kiddie Continuous Performance Test (K-CPT), Home Observation for Measurement of the Environment (HOME)	From 18 to 22 wk. of pregnancy until delivery	547 women, 401 children	400 mg DHA	5 (not available)	54%M	547 women, 396 children	Cornoil and soyoil	5 (not available)	54%M	No effect in MSCA scores. DHA attenuated positive effect of the home environment at 12 mo on general cognitive abilities. Improved K-CPT omission scores. No effect in BASC-2.
	Amminger et al., 2007 Vienna, Austria	Aberrant Behavior Checklist (ABC) (irritability, social withdrawal, stereotypy, hyperactivity, and inappropriate speech)	6 wks	7	840 mg EPA and 700 mg DHA	12.1 (2.7)	100%M	6	Coconut oil	10.5 (3.2)	100%M	Improved inappropriate speech, larger improvement in stereotypy and hyperactivity
	Bent et al., 2011 Davis, USA	Peabody Picture Vocabulary Test, Expressive Vocabulary Test, Aberrant Behavior Checklist (ABC), Behavioral Assessment System for Children (BASC), Clinical Global Impression-Improvement (CGI-I)	12 wks	14	700 mg EPA and 460 mg DHA	5.85 (1.83)	93%M	13	Safflower oil	5.82 (1.42)	85%M	No improvement in hyperactivity (ABC), hyperactivity (BASC), irritability (ABC). Placebo improved Expressive Vocabulary Test, the Social Responsiveness Scale, and the externalizing subscale of the BASC.
	Yui et al. 2012 Ashiya, Japan	Social Responsiveness Scale (SRS) and ABC subscales	16 wks	7	240 mg of arachidonic acid, 240 mg of DHA	10.1 (3.2)	All 2 groups: 92%M	6	Olive oil	19.8 (4.2)	(no group based data)	Improved ABC social withdrawal scores and SRS communication subscale scores.
	Bent et al., 2014 Interactive Autism Network (IAN) Online registry >13,000 families of children affected by ASD	ABC-hyperactivity (parent and teacher), other ABC scales, SRS, CGI-I	6 wks	29	700 mg of EPA and 460 mg of DHA	7.35 (1.03)	90%M	28	Safflower oil	7.08 (1.10)	86%M	Improved hyperactivity (parent ABC-H) in both groups. Improved stereotypy and lethargy subscales of the ABC.
	Voigt et al. 2014 Rochester, USA	CGI-I, ABC, CDI, BASC	6 mos	24	200 mg DHA with high oleic acid sunflower oil to make 500 mg total oil	5.8 (1.8)	83%M	24	250 mg of corn oil and 250 mg of soybean oil	6.5 (2.2)	83%M	Worsened investigator ratings of repetitive/stereotypic behaviors at 6 months. Lower parents (but not teachers) rating of BASC social skills. Improved teachers (but not parents) rating of BASC functional communication.
	Mankad et al., 2015 Toronto, Canada	Pervasive Developmental Disorder- Behavioral Inventory (PDDBI) and externalizing behaviors of BASC-2. Vineland Adaptive Behavior Scales, Second Edition (VABS-II), Preschool Language Scale-4 (PLS-4), CGI-I	6 mos	19	Start 0.75 g of EPA + DHA x 2wks, then 1.5 g	3.9 (range 2.0–4.2)	68%M	19	Olive oil and medium chain triglycerides	3.5 (range 2.0–6.0)	78%M	No effect in PDDBI autism composite scores. Worsened BASC-2 externalizing problem score.
	Boone et al., 2017, Columbus, USA Preterm born toddlers with ASD	Sensory processing Infant/Toddler Sensory Profile (ITSP)	3 mos	13	(Omega-3-6-9 Junior) 706 mg total omega-3 fatty acids: 338 mg EPA, 225 mg DHA; 280 mg total omega-6 fatty acids including 83 mg gamma-linolenic acid; and 306 mg total omega-9 fatty acids	30 mos	53%M	15	Canola oil (124 mg palmitic acid, 39 mg stearic acid, 513 mg li- noleic acid, 225 mg α-linolenic acid; 1346 mg oleic acid)	25 mos	81%M	No effect
	Parellada et al., 2017 Madrid, Spain multicenter, double blinded crossover RCTl	Social Responsiveness Scale (SRS), CBCL, erythrocyte membrane o6/03 ratio	8 wks - 2 wks washout - 8 wks	33	Aged 5–11 years: EPA 577.5 mg, DHA 385 mg; aged 12–17 years EPA 693 mg, DHA 462 mg	Group A 9.39 (3.74)	Group A 75%M	35	Liquid paraffin and vitamin E	Group B 10.03 (3.57)	Group B 91%M	Improved social motivation, communication scores, and CGI-S within the subjects. No treatment effect (treatment-placebo order).
	Keim et al., 2018 Columbus, USA Preterm born toddlers with ASD	Pervasive Developmental Disorders Screening Test II, Stage 2 (PDDST-II), the Brief Infant Toddler Social and Emotional Assessment (BITSEA)	3 mos	15	(Omega-3-6-9 Junior) 706 mg total omega-3 fatty acids: 338 mg EPA, 225 mg DHA; 280 mg total omega-6 FAs, including 83 mg gamma-linolenic acid; and 306 mg total omega-9 fatty acids	30 mos	53%M	16	Canola oil (124 mg palmitic acid, 39 mg stearic acid, 513 mg li- noleic acid, 225 mg α-linolenic acid; 1346 mg oleic acid)	25 mos	81%M	Improved BITSEA ASD scale
	Mazahery et al., 2019 New Zealand	ABC	12mos	VID 19, OM 23, VID + OM 15	Vitamin D3 (VID) 2000 IU, 722 mg DHA (OM)	VID 5.3 (1.5) OM 4.8 (1.5) VID + OM 5.4 (1.3)	VID 84% M, OM 78%M VID + OM 87%M	16	Empty capsules	5.7 (1.0)	81%M	VID + OM > VID, OM improved ABC Hyperact, irritability

2. Importance of n-3 LCPUFA to brain development

Greater than 50% of the dry weight of the human brain is lipid, and, of that, the LCPUFA dominate (Calder, 2016; Skinner et al., 1993; O’Brien and Sampson, 1965). A single fatty acid, the n-3 LCPUFA DHA, makes up 18% of human grey matter (O’Brien and Sampson, 1965). Thus, it is understandable that an energy dense diet, high in fat, is associated with relative brain size among mammals (Leonard et al., 2010). Humans have a diet of 33% fat as compared to 6% fat diet in chimpanzees (Leonard et al., 2010), our closest relative. Consistently, our brain to body weight ratio is also much greater, and there is convincing evidence that this relatively high fat (HF) diet was necessary for humans to evolve their large brains. As the LCPUFA content in aquatic foods is significantly higher (10× in the case of DHA) than liver, muscle or fat tissues of large game animals found in inland plains (Leonard et al., 2010), it has been argued that humans evolved their large brains by eating fish and shellfish in lakeshore environments (Crawford et al., 1999; Cunnane and Crawford, 2003). Brain FAs affect cellular metabolism, membrane structure and permeability, inflammation and synaptic signaling (for excellent review see (Calder, 2016)). The rapidly growing infant brain demands greater than 60% of resting metabolic rate (compared to 20–25% in adults) (Holliday, 1986). To meet these significant metabolic needs, the human infant is born with a high fat mass, which stores the fatty acids necessary to supply building blocks for continued brain growth during postnatal life. During the brain growth spurt between the 3rd trimester of pregnancy and 18 months postpartum (Dobbing and Sands, 1973), the amount of DHA in the brain increases 35-fold (Cunnane et al., 2000). Uptake of DHA, specifically in the form of lysophosphatidyl choline (LPC-DHA) across the blood-brain barrier is dependent on the DHA-transporter MFSD2a, which is highly expressed in the endothelium of brain microvessels (Nguyen et al., 2014). Thus, sufficient dietary LCPUFA supply during pregnancy and postpartum are critical for normal brain development. The placenta is intimately involved in the transport and metabolism of nutrients that pass between mother and fetus. It is not surprising then that the human placenta is highly permeable to FA, also expresses the LPC-DHA transporter MFSD2a (Prieto-Sánchez et al., 2017), and the species with the greatest adiposity at birth (e.g. human, guinea pig) also have placentas with the greatest permeability to FA.

Though humans may have evolved eating diets high in aquatic food, our modern diet has changed. Overfishing, climate change, and pollution – driving fears of mercury contamination – have all impacted seafood availability and our willingness to eat it (Colombo et al., 2020; Oken et al., 2003). Only 10% of women of reproductive age in the U.S. consume the recommended 200 mg/d of n-3 FA (Oken et al., 2003; Smith and Sahyoun, 2005), and n-3 FA levels are lower in women with obesity (Tomedi et al., 2013). This is particularly relevant to fetal neurological development, because maternal n-3 FA deficiency is associated with decreased visual acuity, hypertension, diabetes, ADHD and autism in the offspring (Armitage et al., 2003; Burgess et al., 2000; Connor and Neuringer, 1988; Neschen et al., 2007; Pachikian et al., 2008). According to NHANES data in over 7000 women, only 6% of pregnant women supplement with n-3 FA (Nordgren et al., 2017), suggesting that most of the US population have insufficient n-3 FA intake, potentially placing their offspring at risk of poor neurological outcomes. There may be a role for expanded implementation of n-3 FA supplementation in pregnancy.

2.1. Fatty acid profiles and childhood neurodevelopmental disorders

Increasing evidence suggests that low LCPUFA levels associates with various childhood neurodevelopmental disorders. A meta-analysis of nine studies (Hawkey and Nigg, 2014) and subsequent research (Milte et al., 2015; Parletta et al., 2016) found consistent alterations in blood PUFA levels in children and adults with attention deficit and hyperactivity disorder (ADHD). The studies found lower n-3 LCPUFA blood levels (especially DHA) in all studies in children and adults with ADHD. Some studies reported higher n-6 LCPUFA levels and higher total n-6:n-3 LCPUFA ratio (Milte et al., 2015; Antalis et al., 2006; Laasonen et al., 2009). Similarly, in people with autism spectrum disorder (ASD), lower DHA, EPA and AA and higher total n-6: n-3 PUFA ratio were observed in people with ASD compared to the typically developing population (Mazahery et al., 2017). Parletta et al. reported dose-dependent effects of aberrant LCPUFA levels on severity of the symptoms in children. In children with ADHD, lower DHA, EPA, AA and n-3:n-6 ratio and higher AA:EPA ratio were associated with poorer attention scores. In children with ASD, lower EPA, DHA and AA were associated with higher ASD testing scores (Parletta et al., 2016). Altogether, these data demonstrate an association between low n-3 LCPUFA and neurodevelopmental disorders in children, however cause and effect are unclear. We speculate that low childhood n-3 LCPUFA originate in utero due to poor maternal supply and inadequate placental lipid delivery.

2.2. Role of placental lipid delivery in fetal neurological outcomes

The LCPUFA are synthesized from their essential fatty acid precursors (linoleic (18:2, n-6) and α-linolenic (18:3, n-3) acids) through a series of elongation and desaturation reactions. Neither the fetus nor placenta have sufficient activity of these enzymes to synthesize the substantial amounts of LCPUFA required for fetal development, and thus the fetus depends upon maternal supply and placental transport for n-3 LCPUFA (Makrides et al., 1994; Salem Jr. et al., 1996; Greiner et al., 1997; Chambaz et al., 1985; Haggarty et al., 1997). Indeed, LCPUFA are considered “conditionally essential” during fetal development (Cunnane, 2003), and the placenta may preferentially take up and transport these FA (Haggarty et al., 1997; Haggarty et al., 1999). Using gold standard approaches to measurement of nutrient transport - ex vivo perfusion of human placental cotyledons, (Haggarty et al., 1997; Haggarty et al., 1999) and in vivo stable isotopes (Larque et al., 2003; GilSánchez et al., 2010) - studies show that the LCPUFA DHA and AA are preferentially taken up into the placenta. Following uptake, DHA is transported to the fetal circulation at the highest rates, potentially related to the levels of placental MFSD2a (Prieto-Sánchez et al., 2017), while a large proportion of AA is incorporated into membrane phospholipids (Haggarty et al., 1999; Gil-Sánchez et al., 2010). These data also suggest that the metabolism of FA following uptake into the trophoblast differs between FA, and can affect delivery to the fetus. Recent studies have directly assessed the contribution of FA uptake and metabolism to fetal delivery also using ex vivo perfused placenta (Perazzolo et al., 2016) and in vivo stable isotopes (Gázquez et al., 2020). Computational modeling of stable isotope FA tracer data from these studies determined that only 1–6% of FA taken up by the placenta are transported unmodified to the fetus, while the remainder are oxidized or incorporated into glycerolipids or neutral lipids and stored or repackaged for eventual fetal delivery (Perazzolo et al., 2016; Gázquez et al., 2020). Indeed, it is postulated that this repackaging of lipids is essential for placental FA transport and drives uptake. From this, we can hypothesize that maternal conditions that impact placental FA metabolism also affect fetal delivery, and indeed Gazquez et al. (Gázquez et al., 2020) found that placentas of obese women, which have greater FA esterification and storage (Calabuig-Navarro et al., 2017; Saben et al., 2014), also take up and transport less linoleic acid (LA; 18:2, n-6) and DHA. This has important implications for fetal development, particularly the brain, as discussed above is dependent on a high level of n-3 LCPUFA delivery and may be at risk in pregnancies where placental FA metabolism, thus transport, is compromised. Indeed, offspring of obese mothers have lower DHA levels at birth in some populations and this may be sex-specific (Powell et al., 1866). Altogether these findings are consistent with a critical role for placental FA metabolism in n-3 LCPUFA delivery to the developing fetal brain, and raises concerns regarding potential neurological consequences to fetuses exposed to low n-3 LCPUFA environments, or pregnancies complicated by obesity.

2.3. Maternal obesity and early human brain development

Epidemiological studies, including large-scale national registry studies, identified correlations between maternal obesity and higher risk of various neurodevelopmental disorders, including ADHD (Rodriguez et al., 2008; Chen et al., 2014; Andersen et al., 2018; Kong et al., 2018; Fuemmeler et al., 2019) and ASD (Dodds et al., 2011; Krakowiak et al., 2012; Reynolds et al., 2014; Moss and Chugani, 2014) in offspring. Studies also showed an association between maternal obesity and anxiety and depression in offspring children (Rodriguez, 2010; Colman et al., 2012; Van Lieshout, 2013). ADHD manifests as hyperactivity, impulsiveness, and poor attention, resulting in impairments in working memory, executive function, and impulsive behaviors. Maternal body mass index (BMI) dose-dependently increases risk for children’s ADHD symptoms (Andersen et al., 2018; Kong et al., 2018; Fuemmeler et al., 2019). Four extensive Nordic birth cohort studies found maternal overweight (23–28%), obesity (47–89%), and severe obesity (BMI ≥ 35 kg/m2) (88–95%) increased the risk of ADHD diagnosis in children in a dose-dependent manner (Rodriguez et al., 2008; Chen et al., 2014; Andersen et al., 2018; Kong et al., 2018). Excessive gestational weight gain also increased the risk of ADHD in children (Rodriguez et al., 2008; Fuemmeler et al., 2019).

Autism spectrum disorder (ASD) manifests as difficulties in communication and interaction with other people, restricted interest, and repetitive behaviors (DSM-V, NICHD). ASD is a complex neurological and developmental disorder that begins early in life caused by structural and functional alterations of the brain, likely originated in fetal life. Similar to ADHD, high maternal BMI also associates with higher risk of ASD in children. Pre-pregnancy obesity increases the odds ratio for ASD in offspring by 1.3–2.05-fold (Dodds et al., 2011; Krakowiak et al., 2012; Reynolds et al., 2014; Moss and Chugani, 2014). Excessive gestational weight gain also increases the risk for ASD in children by 10–58% (Dodds et al., 2011; Bilder et al., 2013).

While epidemiological studies found an association between maternal obesity and children’s neurodevelopmental disorders, underlying mechanisms are unknown. As mentioned later in this review, animal studies propose potential mechanisms, though evidence from the human is scarce. Neuroimaging studies of children from pregnancies complicated with obesity begin to reveal functional and structural aberrations in neonatal and childhood brains. Functional studies have shown altered activation or connection in specific regions of the neonatal brain. Higher maternal body fat percentage is associated with decreased functional connectivity between the dorsal anterior cingulate and prefrontal cortices in neonatal brains (Li et al., 2016; Luo et al., 2021). Further, both local (Salzwedel et al., 2018) and global (Spann et al., 2020; Norr et al., 2021) network connectivities were altered in neonates from mothers with high BMI (>25 kg/m², mostly ranging between 30 and 35) compared to those from mothers with BMI 18.5–24.9 kg/m². These studies suggest the aberrant functional connectivity associated with high maternal BMI may originate in the fetal period (Norr et al., 2021).

In contrast to functional studies, little is known how maternal obesity impacts human neonatal or fetal brain anatomy. Children (7–11 years old) from mothers with obesity have reduced hippocampal volume in male but not female offspring (Alves et al., 2020). Similar aberration and sex differences were seen in offspring of mothers with gestational diabetes (Lynch et al., 2021). We do not know how maternal obesity impacts fetal or neonatal brain anatomical development. These studies suggest that the maternal metabolic environment can result in long-lasting changes in offspring’s brain structures and functions. The placenta may play an important mediating role.

2.4. Impact of obesity on placental lipid transport and metabolism – do maternal LCPUFA matter?

The placenta is exquisitely sensitive to the maternal metabolic environment, and the uptake and metabolism of FA are affected by maternal diet, exercise, BMI, and the presence of diabetes (Gázquez et al., 2020; Calabuig-Navarro et al., 2017; Brass et al., 2013; Dube et al., 2012; O’Tierney-Ginn et al., 2015; Pagan et al., 2013; Visiedo et al., 2015; Hutchinson et al., 2020). Maternal obesity (pre-pregnancy BMI > 30 kg/m²) is associated with a decrease in the uptake of oleic acid (a monounsaturated FA), LA, DHA, and reduced expression of several FA transporters (Gázquez et al., 2020; Brass et al., 2013; Dube et al., 2012). Consistent with the findings of Powell et al. (Powell et al., 1866), male offspring of obese women show a more dramatic decrease in placental FA uptake and transporter expression (Brass et al., 2013) which may reflect the high risk growth strategy of males in utero (Eriksson et al., 2010). Though these results may seem incompatible with the fact that offspring of obese women on average are larger and have higher adiposity (Sewell et al., 2006), we postulate that the LCPUFA, which rely heavily on transporters to cross the plasma membrane due to their length and level of unsaturation (Campbell et al., 1996) – are most affected by decreases in transporter number, thus larger babies may still have insufficient LCPUFA delivery, despite adequate, or excess saturated FA. Furthermore, FA uptake rates do not equate to FA delivery to the fetus, and as discussed previously, metabolism of FA within the placenta determines transport (Perazzolo et al., 2016; Gázquez et al., 2019). In fact, decreases in uptake of some FA may be driven by decreases in FA oxidation secondary to impaired mitochondrial function (Chabowski et al., 2006), which is associated with maternal obesity and diabetes (Calabuig-Navarro et al., 2017; Visiedo et al., 2015). Impairments of mitochondrial function are detectable in placentas of obese women as early as 6 weeks of pregnancy, and are associated with decreases in the expression of genes involved in FA oxidation and metabolism (Lassance et al., 2015a). These data in early pregnancy are consistent to what is detectable at term delivery, where placentas of women with obesity have lower levels of β-oxidation rates, higher FA esterification rates, and greater lipid content concentrated in the triglyceride and glycerolipid fractions (Calabuig-Navarro et al., 2017). Similarly, placentas from pregnancies complicated by gestational diabetes have lower overall FA oxidation rates and higher esterification rates (Visiedo et al., 2015; Visiedo et al., 2013). These changes in FA metabolism, combined with the increases in inflammation and oxidative stress characteristic of placentas from women with obesity and/or gestational diabetes (Saben et al., 2014; Radaelli et al., 2003; Ramsay et al., 2002; Roberts et al., 2011; Zhu et al., 2010; Roberts et al., 2009), are typical of a lipotoxic phenotype (Saben et al., 2014). This lipotoxic milieu may impair normal placental processes such as nutrient transport (Memon et al., 1998), hormone production (Lassance et al., 2015b) and thus fetal growth. Indeed, placentas of obese women are less efficient (lower birthweight: placental weight ratio) (Bianchi et al., 2021; Leon-Garcia et al., 2016; Tanaka et al., 2018; Wallace et al., 2012), which may stem from changes in FA metabolism pathways in early pregnancy. Given the recent data showing that such changes in FA metabolism can impact fetal delivery (Perazzolo et al., 2016), we would expect that placental FA transport to the fetus would be impaired in pregnancies of obese and/or diabetic women which is indeed what has been demonstrated using in vivo stable isotope techniques (Gázquez et al., 2020). These changes in placental lipid handling and transport have profound implications for fetal brain development, and may underlie the associations between maternal obesity and risk for poor neurological outcomes in offspring.

These findings raise the question of what can be done to intervene short of weight loss and improving metabolic function before pregnancy (Erickson et al., 2020)? Interestingly, placentas of overweight and obese women randomized to 2400 mg/d of n-3 FA in the form of fish oil starting at 14 weeks of gestation, were found to have 30% lower lipid content (Calabuig-Navarro et al., 2016) and lower inflammatory cytokine levels (Haghiac et al., 2015), suggesting some resolution of the lipotoxic phenotype characteristic of these placentas. In fact, the expression of placenta DGAT1, the rate limiting step in TG synthesis, was inversely related to the change in maternal plasma n-3 FA levels from early to late pregnancy (Calabuig-Navarro et al., 2016), demonstrating the sensitivity of these FA metabolism pathways to maternal n-3 FAs. Fetal growth also improved with maternal n-3 FA supplementation. Neonatal fat-free mass was greater in offspring of women randomized to fish oil, though fat mass was similar to the placebo group (Monthé-Drèze et al., 2021). Increases in fat-free mass may improve metabolic function in later life (Baker et al., 2010). The lack of measurable improvements in placental mitochondrial function raises the question of whether supplementation began too late in gestation, given that placenta mitochondria are impacted by high maternal BMI from early in pregnancy (Lassance et al., 2015b; Zhou et al., 2015). A natural experiment can be conducted by comparing the impact of maternal obesity on placental function and fetal growth in women in a high n-3 FA environment, such as a place where women eat abundant fish from before pregnancy, to a place where maternal n-3 FA levels are low. Indeed, placentas of women with obesity in Hawaii, a state with high fish intake (Baker et al., 2020), do not have higher lipid content than placentas of lower BMI women (Fig. 1), their FA metabolism gene expression pathways do not differ significantly, and maternal DHA levels are 8-fold higher in women in Hawaii vs women in a lower n-3 environment (Alvarado et al., 2018). This data supports the importance of dietary fish in pregnancy, and suggests that high n-3 FA may blunt or ameliorate the impact of maternal obesity on placental lipid handling, which may have implications for fetal brain development and neurological outcomes. We speculate that as women living in a high n-3 FA environment have a chronically high consumption of n-3 FA, it is likely to have a greater ameliorating effect than a fish oil supplement given during pregnancy. In fact, the ½ maximal uptake of DHA and EPA into adipose tissue is greater than 1 year of continuous dietary supplementation, suggesting that short term supplements will be less effective than longer term sustained dietary intake (Katan et al., 1997).

Fig. 1.

Lipid content in placentas of women with and without obesity living in low and high n-3 FA environments (data previously reported in Calabuig-Navarro et al., 2017; Alvarado et al., 2018). Significant effect of n-3 FA environment (P < 0.001), and interaction between environment and maternal BMI (P = 0.009) by two-way ANOVA. Different letters indicate statistically significant differences between groups via Tukey’s multiple comparison test.

3. Fatty acid as a treatment of neurodevelopmental disorders

LCPUFAs have been thought to play critical nutritional roles in various neurodevelopmental and psychiatric disorders such as ADHD, ASD, schizophrenia, major depressive disorder, bipolar disorder, anxiety disorders, obsessive-compulsive disorder, aggression, borderline personality disorder, substance dependence, and anorexia nervosa (reviewed in Bozzatello et al., 2016).

This review focuses on ADHD and ASD as they are at increased risk with maternal obesity and likely have developmental origins in utero. Both conditions have multifactorial or heterogeneous etiologies, including genetics, social, and nutritional factors. Though nutrition may not be the only factor to drive the increasing prevalence of ADHD and ASD, it is considered to play a modulatory role in the onset and severity of the conditions. Based on such epidemiological and mechanistic clues, researchers have attempted LCPUFA supplementation to improve symptoms of ADHD and ASD. These studies vary in supplemental interventions and outcome measures (Table 1). However, studies consistently support benefits of LCPUFAs in reducing adverse symptoms in ADHD or ASD, such as hyperactivity, irritability, and aggressive behaviors.

3.1. ADHD

Nine randomized control trials since 2012 tested efficacy of LCPUFAs on ADHD symptoms (Milte et al., 2012; Perera et al., 2012; Richardson et al., 2012; Widenhorn-Muller et al., 2014; Bos et al., 2015; Matsudaira et al., 2015; Barragan et al., 2017; Cornu et al., 2018; Dopfner et al., 2021) (Table 1). Seven of nine studies reported some improved ADHD symptoms by various forms and contents of LCPUFAs supplements (Milte et al., 2012; Perera et al., 2012; Richardson et al., 2012; Widenhorn-Muller et al., 2014; Bos et al., 2015; Barragan et al., 2017; Dopfner et al., 2021) including reduced impulsiveness and hyperactivity (a Milte et al., 2012; Widenhorn-Muller et al., 2014; Bos et al., 2015; Cornu et al., 2018). The studies used variable doses and a combination of DHA (60–200 mg daily) and EPA (372–1109 mg daily). Placebo (corn-, sunflower-, rose-oil), intervention periods (12 weeks to 12 months), and outcome measures including various ADHD scales, age appropriate cognitive, attention, or behavior scales varied as well. Overall, positive effects of n-3 LCPUFA supplementation were seen in attention (Milte et al., 2012; Bos et al., 2015; Barragan et al., 2017; Cornu et al., 2018), hyperactivity and aggressiveness (Milte et al., 2012; Perera et al., 2012; Barragan et al., 2017), academic performance/cognitive test results (Milte et al., 2012; Perera et al., 2012; Richardson et al., 2012; Widenhorn-Muller et al., 2014), parents-rated behavior (Richardson et al., 2012; Bos et al., 2015; Dopfner et al., 2021), or teacher-rated behavior (Dopfner et al., 2021). It is also notable that various outcome measures were indifferent between LCPUFA treatment and placebo groups. Altogether these studies show therapeutic potential of LCPUFA for ADHD.

One study randomized pregnant women to 400 mg DHA supplements daily or placebo from 18 to 22 weeks of gestation until birth and compared their offspring children’s global cognition, behavior, and attention at age five years using the McCarthy Scales of Children’s Abilities (MSCA), the parental scale of the Behavioral Assessment System for Children, Second Edition (BASC-2), and the Conners’ Kiddie Continuous Performance Test (K-CPT) (Ramakrishnan et al., 2016). There were no group differences for MSCA scores. However, the supplementation attenuated the positive effect of the home environment at 12 months of age on general cognitive abilities in the DHA group compared with the placebo group. On the K-CPT, offspring in the DHA group showed improved executive function scores than the placebo group. The study enrolled the general pregnant population, and was not focused on maternal obesity. The benefit of prenatal supplements targeted at pregnant women with obesity should be assessed as the target population has a higher incidence of ADHD in children.

3.2. ASD

With the known association between low LCPUFA levels and severity of symptoms, investigators have studied if a dietary LCPUFA supplement improves a symptoms of children with ASD. Since 2007, ten RCTs have been reported (Amminger et al., 2007; Bent et al., 2011; Yui et al., 2012; Bent et al., 2014; Voigt et al., 2014; Mankad et al., 2015; Boone et al., 2017; Parellada et al., 2017; Keim et al., 2018; Mazahery et al., 2019). All studies have been relatively small scale (13–73 children). Two recent studies had the largest sample sizes (68 (Parellada et al., 2017) and 73 (Mazahery et al., 2019)). Those studies reported mixed benefits of LCPUFA for the treatment of children with ASD. Five studies reported positive effects in certain symptoms such as social communication (Yui et al., 2012; Parellada et al., 2017), hyperactivity (Mazahery et al., 2019), irritability (Mazahery et al., 2019), stereotypy (Bent et al., 2014) and general autistic symptoms (Keim et al., 2018). Five studies did not find significant benefit or did not show significant differences between treated and control groups (Amminger et al., 2007; Bent et al., 2011; Voigt et al., 2014; Mankad et al., 2015; Boone et al., 2017; Parellada et al., 2017). The authors concluded the lack of sufficient power and suggested a larger-scale study. Aberrant Behavior Checklist (ABC), and Behavioral Assessment System for Children (BASC) has been used in several studies. A recent meta-analysis by Fraguas et al. reported n-3 fatty acid supplementation is more efficacious than the placebo at improving several symptoms of ASD such as hyperactivity, language function, general autistic psychopathology, social-autistic, and stereotypies, and restricted, repetitive behaviors (Fraguas et al., 2019). The effect size is generally small. Therefore, refinement in the dosing protocol of n-3 FA and larger-scale studies are needed to have firmer conclusions. ASD has a heterogeneous etiology. Abnormal lipid metabolism may play a large role in developing ASD in offspring of obese women. Therefore, LCPUFA supplementation may benefit the offspring of obese women compared to children with ASD with genetic etiologies.

Abnormal LCPUFA in offspring of women with obesity, higher prevalence of developmental disorders such as ADHD and ASD, and accumulating reports that LCPUFA supplementation improve symptoms, may rationalize LCPUFA treatment in pregnant women with obesity and their offspring. Most children with ADHD or ASD may only start presenting symptoms after two years of age ~ school age. While LCPUFA supplement in pregnancy may not show immediate benefit right after birth, longer follow-up may be necessary to assess its benefit on neurodevelopmental outcomes.

4. Importance of n-3 FA to fetal brain development - evidence from animal models

4.1. Strengths and limitations of animal models

As research into fetal brain development is limited to external measurements such as MRI as previously mentioned, validated animal models have routinely been used to understand changes occurring during pregnancy. This animal research is relevant and essential due to the obvious ethical issues of research in human fetuses and newborns. Animal models in general however, are not directly comparable to human brain development at the same stage of life and there is stark difference between altricial and precocial species which must be taken into account when designing a study. Other differences, such as animals that produce a litter, must also be accounted for. As the trajectory of brain development differs between species it is important to understand the maturational profiles of brain regions to utilize appropriate animal models. Rodent models of fetal brain development remain the most used due to short gestational period and potential for intergenerational studies, and have been designed to answer specific questions. For example, in models of brain injury, newborn 7 day old rats and 6 day old mice (Rice-Vanucci model) (Rice 3rd et al., 1981) have been shown to have brain maturity similar to that of early third trimester human fetus.

An advantage of using animal models is they can be bred to model specific diseases, such as obesity, and create comparable outcomes to human data. Fetal development defects can also be compared directly with changes in maternal organs and placenta in animals, which can inform pathophysiology of disease. Although much information has been, and will continue to be, gained from commonly used animal models such as mice and rats, the nonhuman primate is believed to be the animal model that most accurately approximates the human, particularly in terms of brain structure. Overall, animal models allow us to modify maternal environments and give us a foundational idea of fetal development in humans.

4.2. Maternal n-3 FA deficiency impacts offspring brain function in animal models

One of animal model advantages is to study impacts of specific maternal nutrient supplementation/deficiency on offspring brain anatomy and function. In general, n-3 LCPUFA supplementation studies have been shown to improve brain function in animals. For example, a number of studies using animal models have shown that both pretreatment with maternal DHA supplementation during fetal and early postnatal life as well as post-experimental DHA supplementation reduces the degree of functional deficits after a hypoxic ischemic injury in 7 day old rat pups (Berman et al., 2010; Zhang et al., 2010). In addition, DHA deficient rodents show downregulation in neural plasticity factors and an increase in brain inflammation (Talamonti et al., 2020) showing the importance of n-3 FA for general brain function.

It is understandable then that adequate n-3 FA intake is critical during pregnancy for fetal brain development, as described throughout this review. Animal studies have demonstrated that deprivation of n-3 fatty acids during pregnancy is associated with visual and behavioral deficits that cannot be reversed with postnatal supplementation. From early studies in the 1980’s, Neuringer et al. used rhesus monkeys to show that low maternal and infant DHA is linked to suboptimal visual acuity and reduced DHA in cerebral cortex and retina of newborn infants (Neuringer et al., 1986). DHA deficient pregnant rats show increased offspring vulnerability to altered brain lipid composition and memory performance when faced with a further LPS challenge (Labrousse et al., 2018), ADHD related behavior (Levant et al., 2010), downregulated glutamate receptors, and upregulated pro-inflammatory TNFα gene expression in the central nervous tissue independent of the effects on membrane composition (Kitajka et al., 2004). Learning deficits in offspring due to maternal n-3 FA deficiency occur independently of visual alterations (Carrié et al., 1999), which indicates it is due to changes in brain function.

4.3. Maternal n-3 supplementation shows improvements in fetal brain development and placental function

As n-3 FA deficiency in pregnancy shows clear associations with aberrant fetal brain development and function, it then follows to understand the effect of therapeutic supplementation. Studies assessing the use of n-3 FA supplementation during pregnancy show significantly improved neurological and placental outcomes in offspring.

In mice, a high n-3 FA diet during pregnancy elevates mRNA expression of MFSD2A in the fetal brain which correlated with brain DHA accretion at 12.5 and 18.5 weeks, compared to low or very low PUFA supplements (Akerele and Cheema, 2020). DHA has also been shown to be increased in the cerebellum of female offspring compared to males which may account for cognitive-based sex differences we see in children of n-3 FA deficient mothers (Feltham et al., 2019). High n-3 FA diet during pregnancy also increased the mRNA expressions of neurotrophins BDNF, TRkB and CREB during gestation (Akerele and Cheema, 2020). Increased neurotrophins promote synaptic plasticity and neuronal survival which have an effect on memory, cognition and ultimately behavior, showing that n-3 FA levels during pregnancy may be linked to behavioral outcomes in offspring, starting from fetal age. The effects on placentas of these same mice showed elevated mRNA expression of the FA transporters EL and FABPpm at both fetal ages also which account for the increased fatty acid uptake and transport, suggesting that n-3 intake itself improves placental nutrient transfer to offspring in this model (Akerele and Cheema, 2020). Changes in placental FA transporters were not demonstrated in n-3 supplementation RCT in humans (Calabuig-Navarro et al., 2016), however those were initiated in the second trimester as opposed to pre-pregnancy in the mouse model. Akerele et al. also found that increased n-3 FA before and during pregnancy (via fish oil supplementation) increased incorporation of n-3 FA into the placenta itself, which coincided with a decrease in pro-inflammatory cytokines indicating improved placental function (Akerele and Cheema, 2018). As placental interleukin-6 (IL-6) cytokine transfer to the fetus has implications for fetal brain development and behavior in rodent models (Wu et al., 2017; Dahlgren et al., 2006; Samuelsson et al., 2004; Srivastava et al., 2021) and potentially humans (Zaretsky et al., 2004), this supports the therapeutic potential of n-3 supplementation for maternal inflammatory environments such as obesity.

4.4. N-3 supplementation in animal models of obesity

Obesity during pregnancy is most commonly modelled using animals fed a high-fat diet or specifically bred for obesity phenotypes. Regardless of model used, maternal obesity consistently shows offspring psychiatric outcomes similar to that of human data such as increased ASD and ADHD type outcomes as measured by social interaction (Graf et al., 2016; Kang et al., 2014) and hyperactivity (Kang et al., 2014; Ruegsegger et al., 2017; Fernandes et al., 2012), as well as other neurobehavioral outcomes such as impaired learning and memory (Page et al., 2014; Lépinay et al., 2015), anxiety (Bilbo and Tsang, 2010; Sasaki et al., 2013) and depression (Sullivan et al., 2010). These behavioral impairments are often exacerbated in male offspring.

Despite numerous studies on the effects of n-3 fatty acid deficiency, and supplementation, few studies have examined the therapeutic potential of n-3 FA in conjunction with obesity, particularly during pregnancy. To our knowledge, there are no studies assessing brain development and behavior and associated placental changes in this model. However, improvements in other offspring outcomes including metabolism have been observed.

In rats, fish oil supplementation with HF diet during pregnancy (but not lactation) has been shown to improve insulin sensitivity in male offspring (Albert et al., 2017) as well as reductions in liver inflammation and adiposity (Ramalingam et al., 2018). Despite improvements in insulin signaling, other outcomes such as offspring weight and food intake did not change for either study. Interestingly, fish oil supplementation did not improve any outcomes for offspring from control diet fed dams, which could indicate a diet-dependent response in the study by Albert et al. (Albert et al., 2017). It should be noted however that this study design shows no difference in maternal weight prior to or during pregnancy, so effects observed would be to counteract a HF diet rather than pre-pregnancy weight or BMI in relation to human data. In the latter study, postnatal fish oil supplementation in pups from mothers fed a HF diet during pregnancy did not completely reverse negative effects indicating the importance of adequate maternal nutrition during pregnancy for long term offspring health consequences (Ramalingam et al., 2018).

5. Conclusions

Current research using n-3 supplementation to mitigate the impacts of maternal obesity is promising, and research into its effects on fetal brain development and subsequent behavioral modifications are necessary. The placenta has been shown to be critical in the efficient transport of n-3 FA, and whether n-3 supplementation during pregnancy can improve transfer to the fetus in models of obesity have yet to be determined. In children, various neurodevelopmental disorders especially ADHD and ASD associate with abnormal maternal and offspring lipid profiles. n-3 FA supplementation trials for children with ADHD or ASD have shown promising benefit to improve various core symptoms of those conditions.

A major benefit of animal studies, in regards to n-3 supplementation, is the ability to adjust diet before and during pregnancy, whereas in humans, supplementation studies usually begin in the second trimester making it hard to understand the impact of the first trimester placental and fetal development. Animal studies provide the opportunity to assess underlying mechanisms to connect maternal obesity, fetal brain development, and childhood neurodevelopmental features. Although brain development of the fetus accelerates towards the end of pregnancy, the impact of early placental development may affect lipid handling and n-3 supply during this period, as illustrated in our conceptual model (Fig. 2).

Fig. 2.

Conceptual model of how placental lipid metabolism mediates the effect of the maternal environment on fetal brain development. Levels of maternal n-3 LCPUFA (e.g. DHA, in green), are affected by adiposity and lipid stores, maternal FADS2 genotype, and diet, particularly fish intake. DHA is taken up into the placenta by multiple fatty acid transporters that may be fewer in placentas of obese women. Once taken up into the trophoblast, DHA can be oxidized in the mitochondria (FAO), esterified (FA EST) and stored in lipid droplets (LD) or esterified into phospholipids (PL) and lysophosphatidyl choline (LPC) and incorporated into cell membranes. A key form of DHA for fetal delivery and brain uptake is LPC-DHA These metabolic processes impact DHA available for transfer to the fetus and potentially neurological development.

Our review finds pregnancy to be a promising and critical period to intervene to improve offspring neurodevelopmental outcomes associated with maternal obesity. Improvements in placental lipid handling in women with obesity in the setting of high maternal n-3 FA intake suggests that dietary interventions in these pregnancies may be effective at improving outcomes.