Role of Omega-3 Fatty Acids in Maternal, Fetal, Infant and Child Wellbeing

Ellen Mozurkewich; Deborah R Berman; Julie Chilimigras

Expert Rev of Obstet Gynecol. 2010;5(1):125-138.

Perinatal Depression

Evidence from Epidemiologic Studies

Increases in depressive disorders have been observed since the 1950s, coinciding with the period of dietary change and increase in omega-6 to omega-3 polyunsaturated fat ratio, total fat, saturated fat and linoleic acid.^[2] Hibbeln and Salem have hypothesized that increases in the consumption of linoleic acid-rich vegetable oils have contributed to the observed increase in depression over the past century in industrialized societies.^[59] A North Finland birth cohort study demonstrated that women who ate fish once per month or less were 2.6-times more likely to develop depression compared with women who ate fish weekly or more often.^[60] In a recently published comparison of orbitofrontal cortex DHA in the brains of deceased individuals with and without major depressive disorder (MDD), selective deficits of DHA in these brain regions were noted in individuals with MDD compared with controls. This difference was greater between women with and without MDD than among men.^[61]

During gestation, fetal brain growth requires maternal mobilization of essential fatty acids. In particular, the fetal demand on DHA in the third trimester is estimated to be 67 mg/day. In the face of often inadequate dietary DHA and EPA intake, depletion of maternal fatty acid stores may occur. Some investigators have hypothesized that this maternal omega-3 fatty acid depletion during pregnancy and lactation may play a causal relationship in the development of depression during pregnancy and postpartum.^[62] This possible relationship is supported by evidence from animal studies and observational literature. In an animal model of pregnant rats fed diets deficient in omega-3 fatty acids, the brain regions responsible for mood and cognition were selectively depleted of DHA during the reproductive cycle.^[15] Additionally, parous rats fed the omega-3 fatty acid deficient diet exhibited neurobiological effects that have been associated with depression in humans.^[63]

There are epidemiologic data to support the idea that DHA alterations affect postpartum depression as well as antepartum mood alterations. In a Dutch cohort, women experiencing postpartum depressive symptoms demonstrated slower normalization of DHA status after delivery.^[64] In a cross-national analysis, Hibbeln found that the prevalence of postpartum depression was inversely correlated with the DHA (but not EPA) content of the mothers' breast milk.^[25] Likewise, in a New Zealand cohort of 380 women who completed the Edinburgh Postnatal Depression Scale (EPDS) at 6 months postpartum, a 1% increase of plasma DHA was associated with a 59% reduction in reporting of depressive symptoms.^[65]

Evidence from Clinical Trials

Prevention Trials In a placebo-controlled, randomized trial among 89 women who were not selected based on predisposition or risk for postpartum depression, low-dose DHA supplementation (200 mg) commencing at delivery and continuing for 4 months postpartum did not prevent postpartum depressive symptoms.^[66] In an open-label study of fish oil supplementation (EPA plus DHA totaling 2.96 g/day) begun at 34–36 weeks' gestation among seven women with a history of postpartum depression, Marangell found no reduction in depression recurrence compared with historical controls.^[67] This intervention began late in pregnancy, which may have limited its ability to prevent depression recurrence. An additional recent randomized, controlled trial supplemented pregnant women with low baseline dietary fish intake with low-dose (200 mg) DHA supplementation, low-dose (200 mg) DHA supplementation plus arachidonic acid, or placebo. This study found no difference between groups in Edinburgh Postnatal Depression Scale score postpartum, or during pregnancy.^[68]

Treatment Trials Freeman and colleagues conducted two small, randomized pilot trials of omega-3 fatty acids for treatment of depression during pregnancy and postpartum.^[69,70] These studies lacked a placebo control group and all subjects received omega-3 fatty acids containing a 1.5:1 ratio of EPA to DHA in varying doses. A 40–50% reduction in depression scores, as measured by the Edinburgh Postnatal Depression Score, was achieved with this treatment at all doses in both the pregnant and postpartum populations.^[71]

Subsequently, there have been three small placebo-controlled, randomized, controlled trials exploring the possible utility of omega-3 LC-PUFA in the treatment of perinatal depression. Freeman et al. randomized 59 perinatal women with MDD to either EPA and DHA (1.9 g/day) or placebo for 8 weeks. Supportive psychotherapy was provided to all subjects. No statistically significant benefits of omega-3 fatty acids over placebo were seen. Psychotherapy may have limited the ability to detect an effect of omega-3 fatty acids.^[72] Similar findings were seen in Rees' 2008 double-blind, randomized, placebo-controlled trial in which 26 women with major depression during the perinatal period received either fish oil or placebo for 6 weeks. There was no significant difference in depression scores between those receiving fish oil and those receiving placebo.^[73]

By contrast, Su et al. demonstrated a positive correlation between omega-3 fatty acid supplementation during pregnancy and lowered depression scores.^[74] This trial examined the efficacy of omega-3 LC-PUFA for the treatment of depression during pregnancy over 8 weeks. The study recruited 36 pregnant women with MDD who were not receiving psychotropic agents 1 month prior to or during the study period. The study interventions were EPA plus DHA totaling 3.4 g/day or placebo capsules containing olive oil ethyl esters. Women receiving omega-3 fatty acid supplementation experienced significant improvement in the Hamilton Rating Scale for Depression both at 6 and 8 weeks after initiation of the treatment.^[74] These conflicting findings between trials may result from differences in the timing of initiation of fish oil supplementation, in that these supplements may require several months in order to manifest a beneficial effect, or from differing doses and combinations of EPA and DHA.

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Table 1. Omega-3 fatty acids and industrial contaminants in commonly eaten fish and shellfish.
Type	EPA + DHA (mg/serving) (oz)	EPA + DHA (mg/100 g) (3.5 oz)	Mercury (µg/g) (ppm)	PCBs (ng/g) (ppb)
Anchovy	1165 (2)	2055	< 0.05
Catfish, farmed	253 (5)	117	< 0.05	< 50
Cod, Atlantic	284 (6.3)	158	0.10
Fish burger (fast food)	337 (2.2)	546	< 0.05	8
Fish sticks, frozen	193 (3.2)	214	< 0.05
Halibut	740 (5.6)	465	0.25
Herring, Atlantic	1712 (3)	2014	< 0.05
Mackerel, Atlantic	1059 (3.1)	1203	0.05
Mackerel, King	618 (5.4)	401	0.73
Mahimahi	221 (5.6)	139	0.15
Pollock, Alaskan	281 (2.1)	468	< 0.05
Salmon, farmed	4504 (6)	2648	< 0.05	15–51
Salmon, wild	1774 (6)	1043	< 0.05	0.5–5
Sardines	556 (2)	982	< 0.05	22–57
Shark	583 (3)	689	0.99
Snapper	546 (6)	321	0.19
Swordfish	868 (3.7)	819	0.98
Trout	581 (2.2)	935	0.07	11
Tuna (light/skipjack)	228 (3)	270	0.12	45
Tuna (white/albacore)	733 (3)	862	0.35	100
Clams	241 (3)	284	< 0.05	2–3
Crab	351 (3)	413	0.09	6
Lobster	71 (3)	84	0.31
Mussels	665 (3)	782	< 0.15	0.8–7
Oysters	585 (3)	688	< 0.05	0.8–17
Scallops	310 (3)	365	< 0.05
Shrimp	267 (3)	315	< 0.05	0.2–2

DHA: Docosahexaenoic acid; EPA: Eicosapentaenoic acid; PCB: Polychlorinated biphenyls; ppb: Parts per billion; ppm: Parts per million.
Adapted from.^[101]

Table 2. Results of clinical trials of omega-3 fatty acid supplementation.
Parameter	Results
Preterm birth:
< 37 weeks	No benefit*
< 34 weeks	Likely benefit^§
Intrauterine growth restriction (small for gestational age)	No benefit
Preeclampsia	No benefit
Perinatal depression:
– Prevention	No benefit
– Treatment	Conflicting results^¶
Neurodevelopmental outcomes:
– Term	Conflicting results
– Preterm	Conflicting results
Prevention of allergic disease	Conflicting results

*The majority of the available clinical trials show no benefit for the intervention.
^§The majority of the available clinical trials show a benefit for the intervention.
^¶Clinical trial results are mixed, with some trials showing benefit and others not.

Box 3. Biologic activities of omega-3 fatty acids.
Decrease proinflammatory cytokine production Precursors of resolvins and neuroprotectins Improve membrane fluidity May counter or promote apoptosis, depending on circumstance Regulate gene expression Act as antioxidants Quicken neurotransmission Modulate intracellular signaling

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