Assessing Omega-3 Fatty Acid Supplementation During Pregnancy and Lactation to Optimize Maternal Mental Health and Childhood Cognitive Development

Chelsea M Klemens; Kataneh Salari; Ellen L Mozurkewich

Disclosures

Clin Lipidology. 2012;7(1):93-109. 

In This Article

Biological activities of omega-3 fatty acids in the adult brain & their relationship to maternal depression in pregnancy & postpartum

Lipids are the most predominant substances in the mammalian brain.[15] These lipids are in the form of saturated, monounsaturated and PUFAs. DHA is the most abundant of all omega-3 fatty acids in the brain, comprising 10–20% of the entire fatty acid composition.[15] In the brain and retina, DHA is found primarily in the form of membrane phospholipids and regulates membrane fluidity and membrane-bound enzymes.[16] These DHA-induced property changes in the membrane impact cell signaling by altering the binding or release of neurotransmitters.[17] More specifically, in cultured rat astrocytes, DHA has been implicated in the inhibition of glutamate uptake by cortical astrocytes.[18]

There have been a number of published animal studies modeling maternal dietary shortages of omega-3 fatty acids during gestation, investigating the effect of this deprivation on the maternal brain. In one such study, Chalon et al. demonstrated that dietary deficiency of ALA across two generations of breeding female rats resulted in dysregulation of dopamine and serotonin transmission in maternal rat brains.[19]

In another series of dietary deprivation studies, Levant et al. showed that when dietary deficiency of omega-3 fatty acids is combined with the depletion of DHA that occurs during pregnancy and lactation in the rat model, specific brain regions lose more DHA than others.[20] In an experimental model involving female rats fed a low ALA diet across two reproductive cycles, Levant et al. showed that the frontal cortex and temporal lobes (the areas involved in cognition and affect) as well as the caudate–putamen appear to suffer the greatest reduction in DHA levels, suggesting that certain neuronal systems are more sensitive to DHA depletion.[20] In a subsequent set of experiments, the same team of investigators constructed a rodent model of DHA depletion and perinatal depression.[21] In this rat model, female rats in the intervention group were fed ALA deficient diets across two reproductive cycles; control animals were fed a diet with adequate ALA.[21] This dietary manipulation resulted in decreased brain DHA content in the intervention group compared to controls, which was associated with decreased hippocampal BDNF gene expression, altered serotonin content in some brain regions, and increased hypothalamic pituitary axis response to stress.[21] In a later set of experiments using the same model, these investigators found that animals fed the ALA-deficient diet had a 20–22% reduction in brain DHA compared with controls. DHA depletion in the brains of the parous rats was shown to be associated with a decrease in the density of D2-like dopamine receptors in the ventral striatum.[22] These findings are thought to replicate observed biochemical changes in the brains of depressed humans.[21,22]

The actions of DHA as a neuroprotectant have also been described through its effect on phosphatidylserine synthesis.[23] Phosphatidyl serine is made from DHA-containing substrates and is important in preventing inappropriate cell death and supporting neuronal differentiation.[23] In retinal pigment epithelial cells, DHA also acts indirectly to protect against oxidative stress through the enzymatic production of neuroprotectin D1 (NPD1).[24] NPD1 increases production of antiapoptotic proteins and decreases proapoptotic proteins of the Bcl-2 family.[24] NPD1 also works through neuroprotective gene expression mechanisms that suppress the ability of Aβ42 to activate proinflammatory genes.[16] A large body of evidence has shown that DHA actually modulates several genes with diverse functions that include cell proliferation, DNA binding, transcriptional regulation, transport, cell adhesion and a number of others. This demonstrates that DHA is capable of significantly impacting cell development, function and maturation.[9,25,26]

Another important role for DHA is the modulation of inflammation in the brain.[25] Animal models have demonstrated that during states of neuroinflammation, microglial cells are first-responders, acting to initiate a series of events that eventually leads to the breakdown of membrane glycerophospholipids and the release of ARA and DHA.[25] ARA is then oxidized into proinflammatory prostaglandins, leukotrienes and thromboxanes.[25] DHA, on the other hand, is enzymatically converted into D-series resolvins and neuroprotectins, which inhibit the formation of these proinflammatory prostaglandins, leukotrienes and thromboxanes.[25] DHA and its metabolites also act to decrease inflammation by inhibiting NF-κB, a transcription factor whose activation upregulates proinflammatory cytokine production. Its inhibition prevents the release of cytokines and curbs leukocyte activity.[25] While neuroinflammation does serve a protective purpose against CNS insults, DHA acts to modulate the inflammatory effect of ARA-derived inflammatory mediators and therefore protects the brain from unopposed inflammation.[25]

The ability of omega-3 fatty acids to modulate the inflammatory response, combined with the established relationship between inflammation and depression, has provided a link between omega-3 fatty acids and mental health. Recent evidence suggests that inflammation plays a major role in the pathogenesis of depression; elevated levels of proinflammatory cytokines have been observed in many depressed individuals.[27] An association between elevation of inflammatory cytokines and depression in nonpregnant and nonpostpartum individuals has been well established;[28,29] however, relatively few studies have investigated whether the inflammatory response might play a role in perinatal depression.[30,31]

In a longitudinal observational study of 91 healthy pregnant women, Maes and colleagues assessed maternal serum cytokines IL-6, IL-6 receptor (IL-6R), gp130 (the IL-6 signaling protein), IL-1R antagonist (IL-1RA) and leukemia inhibitory factor receptor before delivery and 1 and 3 days after delivery.[32] The women also completed the Spielberger State–Trait Anxiety Inventory (STAI) and the Zung Depression Rating Scale (ZDS) at each time point.[32] Although there was no overall relationship between the inflammatory markers studied and the absolute values of depression or anxiety scores, the investigators found that mothers with greater postnatal increases in the ZDS had significantly higher levels of IL-6 and IL-1RA. Similarly, mothers with greater increases in the STAI had significantly higher IL-6 and IL-6R.[32] Subsequently, Corwin and colleagues investigated the relationship between depressive symptoms and inflammatory markers in 25 healthy postpartum women.[30] Participants completed the Centers for Epidemiologic Studies Depression Scale on day 28 following delivery; a score of >11 was used as a measure of significant depressive symptoms.[30] Participants also gave urine samples for measurement of IL-1β and IL-6 on days 7, 14 and 28. The authors found that women with significant depressive symptoms on day 28 had significantly elevated IL-1β levels on day 14, compared with women without significant depressive symptoms.[30]

In observational studies among nonpregnant individuals, higher plasma omega-3 fatty acid levels have been found to be associated with lower levels of inflammatory cytokines and higher levels of anti-inflammatory cytokines. For example, in a community-based sample of 1123 individuals' plasma PUFA levels and circulating inflammatory markers, it was found that PUFAs, especially omega-3 fatty acids, were independently associated with lower levels of proinflammatory markers (IL-6, IL-1RA, TNF-α and C-reactive protein) and higher levels of anti-inflammatory markers (soluble IL-6R, IL-10 and TGF-β).[33]

As DHA is a major building block of the brain, studies of the effects of omega-3 fatty acids on brain function have, in the main, focused on DHA and omitted discussion of EPA. EPA has been detected in trace amounts in the brain where it may be enzymatically converted to DHA or participate in a host of biochemical activities.[34,35] In an animal model in which 3-week-old male rats were fed highly purified ethyl EPA, EPA was shown to modulate synaptic plasticity and activates the PI3-kinase/Akt pathway – activities that are thought to protect against neurodegeneration.[34]

Like DHA, EPA may suppress the inflammatory response. One study comparing 8 weeks of dietary supplementation with fish oils with varying ratios of EPA:DHA among female mice (from 6 weeks of age onward) has suggested that suppression of proinflammatory cytokine production may be greatest with those oils with a high EPA:DHA ratio.[36] However, this relationship has not been confirmed in all studies. For example, an in vitro study comparing effects of EPA with DHA on liposaccharide-stimulated THP-1 macrophages, found that pretreatment of cell cultures with DHA suppressed proinflammatory cytokine production (IL-1β, IL-6 and TNF-α) more efficiently than pretreatment with EPA.[37] Therefore, it is uncertain what composition of omega-3 fatty acids would be most beneficial in decreasing inflammation and improving mental health.

EPA is also the metabolic precursor of the E-series resolvins; resolvin E1 (RvE1) and RvE2.[38] RvE1 possesses potent anti-inflammatory activities at nanomolar levels, reducing PMN infiltration and synthesis of proinflammatory cytokines in a dorsal pouch model.[38] In a mouse model of inflammatory pain, RvE1 modulated synaptic plasticity in the dorsal horn of the spinal cord;[39] however, the activities of RvE1 in the brain have not been well characterized.

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