Fish Oil for Women's Health, Pregnancy and Fetal Development

A comprehensive look at the recent research into the role omega-3 plays in women's health. Particular detail into the importance of omega-3 during pregnancy and early development.

 

Key Points:

1. Fish oil reduces inflammation: A reduction in inflammation led to a 28 to 45% increase in implantation rate.
2. Fish oil diminishes post-partum depression.
3. Fish oil reduces menstrual pain.
4. Fish oil reduces the likelihood of postmenopausal hot flushes.
5. Twenty to Twenty-Five percent of the adult brain is omega fatty acids.
6. Fish oil increases gestation length.
7. Fish oil increases birth rate.
8. Fish oil improves eye hand co-ordination and visual development.
9. Fish oil leads to higher novelty preference on visual recognition memory and higher scores of verbal intelligence quotient.
10. An increase in maternal omega-3 led to higher scores on child standardized intelligence.
11. Higher placental cord DHA concentration led to better visual, cognitive, and motor development.
12. Fish oil supplementation reduces blood pressure and modulates cardiovascular risk.
13. Maternal fish oil decreased the risk of metabolic disorders such as type I diabetes in the developing offspring.
14. Omega-3 fatty acid supplementation can help prevent allergic disease in children at risk.
15. The possible relevance of the omega-6 AA for development and function is yet to be confirmed in clinical settings. There is limited evidence for a beneficial effect of AA on brain development and function, when it is given in combination with DHA to term infants.

OMEGA-3 FATTY ACIDS FOR FERTILITY, MENOPAUSE, MENSTRUAL PAIN & POST-PARTUM DEPRESSION

Increase in Fertility
Research suggests that high carbohydrate intake, which increases blood insulin levels can decrease fertility; however an elevation in the ratio of prostacyclin to thromboxane from omega-3 fatty acid intake can increase fertility. Rubinstein et al.1 studied 298 infertile patients in a randomized, double- blind, placebo-controlled study. In addition to ovarian stimulation, half the women received a daily dose of 100 mg aspirin to reduce inflammation. This reduction in inflammation subsequently increased the rate of pregnancy from 28% to 45% and doubled implantation rate. Similarly to aspirin, fish oil decreases endometrial cell thromboxane production which could improve implantation rate. Research has also shown that methylpredinsolone can improve the pregnancy and implantation rates in IVF patients2 and it is thought they do so by inhibiting phospholipase A2 thus preventing the release of AA and therefore inhibiting the production of inflammatory eicosanoids TXA2 and PGE2. Research is ongoing to determine the validity of fish oil for improvements in fertility but the current recommendation is 1250 mg EPA + DHA3.

Postpartum Depression
Lower DHA and a higher omega-6 to omega-3 ratio have been reported in women who develop postpartum depression4, 5. Furthermore, evidence from the diversity in dietary intakes across the planet indicates that the intake of omega-3 fatty acids (FA) is inversely related to morbidity from postpartum depression6 and that countries with low omega-3 intake have a forty-fold higher prevalence of postpartum depression than those with the high intakes7. A few intervention trials have been done to assess omega-3 FA modulation of post-partum depression. Intake of up to 2.8 g/day has shown a significant reduction in depression during pregnancy and the postpartum period8,9. In a second, eight-week, double-blind, placebo-controlled trial omega-3 PUFAs (3.4 g/d) was compared with placebo in pregnant women who had major depressive disorder. Subjects in the omega-3 group had significantly lower depression scores at weeks six and eight, a significantly higher response rate, and a higher remission rate. At the study end point, subjects in the omega-3 group also had significantly lower depressive symptom ratings on two other scales for depression10.

Painful menstruation & menopause
Seventy women took 1 g of omega-3 twice daily for an entire month, then 8 days prior to and 2 days during menstruation. Omega-3 supplementation successfully reduced the quantity of non-steroid anti-inflammatory drugs (NSAIDs) and acetaminophen necessary to reduce menstrual pain11. In another clinically controlled double blind placebo trial a dietary supplement with fish oil, enriched with, or in combination with vitamin B12 substantially reduced menstrual discomfort among Danish women. The prevalence of menstrual pain was inversely associated with dietary fish oil content and B12-vitamin intake. It was hypothesized that because menstrual cramps are prostaglandin mediated, and therefore controlled by dietary fats; fish oil supplements could be a treatment option for the prevention of dysmenorrhea. Indeed, in the present trial, three months of fish oil treatment led to a significant reduction in the number of reported menstrual symptoms, interferences with daily activities and led to a highly significant reduction in reported pain12.

Polyunsaturated fatty acids (PUFAs) might also reduce hot flushes in menopausal women. In a double-blind, randomized, placebo-controlled trial with crossover design a supplement containing 400 mg of fish oil was assessed in postmenopausal women with more than five troublesome hot flushes per day. It was hypothesized that omega 3-fatty acids could reduce hot flushes through their influence on neuronal membranes and/or the modulation of the neurotransmitter function. The PUFA supplement was in fact able to significantly reduce the number of hot flushes13.

OMEGA-3 FATTY ACIDS FOR PREGNANCY AND FETAL DEVELOPMENT

The brain is made of fat
Neural development lasts well into late adolescence, but several major developmental processes occur during prenatal life14. One of the major components of the brain that is highly involved in neural development is lipids. In fact, about 50% of the dry weight of the adult brain consists of lipids of which 20–25% is long-chain polyunsaturated fatty acids (LC-PUFA)15. The LC-PUFAs that make up the greatest percentage of fatty acids in the brain are the omega-3 fatty acid docosahexaenoic acid (DHA) and the omega-6 fatty acid arachidonic acid (AA), both of which are formed from their fatty acid precursors, alpha-linolenic acid (ALA) and linolenic acid (LA), respectively. The overall capacity to convert ALA to EPA and DHA is very low, and therefore preformed DHA and EPA must be obtained from dietary sources16. The major sources of the omega-3 LC-PUFAs are fish and seafood, whereas seed oils, eggs, and grain fed animal meat contain the greatest amount of omega-6 FAs17. The average diet is however very low in omega-3 compared to omega-6 which suggests that omega-3 supplementation could be necessary to ensure adequate amounts of this necessary FA18,19. LC-PUFAs have several biological functions in brain development and function, that include among others: the maintenance of membrane structure and function, the synthesis of eicosanoids (local hormones participating in a number of physiological and pathophysiological conditions, such as the initiation of parturition and immune responses), and finally, LC-PUFAs are involved in gene expression15, 20.

Long chain polyunsaturated fatty acids and pregnancy
Research has determined that LC-PUFAs have an effect on the developing fetus and also directly affect pregnancy itself. The LC-PUFA demand of the developing fetus is very high and often challenges maternal capacities. This is particularly true for the last ten weeks of gestation when about 90% of fetal fat disposition occurs21. In order to cope with the fetal fatty acid demands, maternal fatty acids in plasma phospholipids increase by 50% during the course of pregnancy but the levels of AA and DHA increase relatively less22,23. These higher levels of fatty acids do not occur due to changes in dietary behaviour, but are due to an accelerated breakdown of maternal fat deposits24,25. This suggests that fetal LC-PUFA supply does not only depend on LC-PUFA content of the maternal diet during pregnancy but also on LC-PUFA content of the diet prior to pregnancy. Fatty acids cross the placenta by simple diffusion and via the action of fatty acid binding proteins (FABPs)26,27. This selective transplacental transport results in maternal LC-PUFA levels 300 to 400 times lower than they are in the fetus, that can lead to a state of fatty acid deprivation in the female mother28,29. After about the third trimester and onwards, the fetus is able to synthesize both AA and DHA on its own; however, its capacity to synthesize DHA is significantly lower than for AA. This suggests that from the third trimester of pregnancy onwards the fetus and infant are less dependent on dietary omega-6 FA AA than they are on the dietary omega-3 FA DHA26, 28.

LC-PUFAs and gestation length
Premature birth poses significant health risks to the new baby and is the most recognized cause of neonatal mortality, morbidity and long-term handicaps/low IQ3. A number of observational studies30 have confirmed the association of high-fish intake with a slightly prolonged gestation. It is thought that omega-3 fatty acids modify the balance of production of prostaglandins involved in the initiation of labor and thereby are able to prolong gestation. Following these observations, several randomized controlled intervention studies have assessed omega-3 LC-PUFA supplementation in pregnant women. Two recent meta-analyses indicated that gestation is prolonged by an average of 1.6–2.6 days with omega-3 supplementation31,32. A randomized double-blind, placebo-controlled trial, published after these meta-analyses discovered that supplementation with 300 mg of DHA from fish oil from gestation week 24 resulted in a significantly longer gestation (six days on average)33. In another study fish oil supplementation from the 30th week of gestation onward was shown to reduce the risk of premature birth by 40-50%, increase the length of pregnancy by four days and resulted in babies 100 g heavier than controls34. Furthermore, an additional meta-analysis of four randomized control studies demonstrated a reduced risk of early preterm delivery with LC-PUFA supplementation in women with high-risk pregnancies35. Recent results from a study on pregnant women with previous pregnancy complications revealed that supplementation with fish oil as a source of LC-PUFA delays the onset of delivery. Fish oil in pregnant women who had experienced preterm delivery, intrauterine growth retardation, or pregnancy-induced hypertension in a previous pregnancy reduced their hazard rate of spontaneous delivery by 44%36.

Fetal growth
Omega-3 LC-PUFA intake during pregnancy has also been associated with a trend toward greater growth measures at birth by some observational studies30, 37, 38. Recently, two randomized trials showed slightly higher rates of birth weights and significantly greater head circumference with omega-3 supplementation31 ,32. In a recent prospective cohort study, data on maternal fish/omega-3 LC-PUFA intake and the status of 676 women were obtained at the first trimester, the second and third of pregnancy. Infant birth weight was measured immediately following hospital delivery. The study revealed that women who did not eat fish during the third trimester and those who had a low EPA intake during the third trimester had an association with a higher risk of low birth weight39.

Hypertension and pre-eclampsia
Hypertension complicates about 6% of pregnancies in the developed world and a cross-sectional case control study recently found that pregnant women with low levels of omega-3 fatty acids were 7.6 times more likely to have pre-eclampsia than those with high levels of these PUFAs40. Furthermore, this cross-sectional study revealed that a moderate increase in the proportion of omega-3 fatty acids consumed reduced the risk for pre-eclampsia by 46%40. Meta-analytical reviews confirm a dose-dependent relationship between omega-3 fatty acid intake and blood pressure outside pregnancy40,41 and recent evidence suggests that blood pressure control later in life may also be affected negatively by inadequate maternal and neonatal intake of omega-3 fatty acids42.

Maternal LC-PUFA supplementation or PUFA-enriched formula and fetal outcome
Maternal omega-3 fatty acids status appears to correlate with fetal outcome. Adequate levels of omega-3 fatty acids in pregnant women are correlated with enhanced fetal cognitive and behavioural functioning43-45, improved sleep behaviour46, and less risk of metabolic disorders such as type I diabetes in the developing offspring47.

A) LCPUFA and visual development
When infants are born their visual system is poorly developed, however, development occurs quickly during the first year of life48, 49.  Numerous studies have evaluated the effect of DHA status on the developing visual system. Malcolm et al.50 provided fish oil during pregnancy and found that the DHA status of infants at birth was related to the maturity of visual evoked potential at 2.5 and six months of age. Furthermore, another study discovered that eye-hand coordination at the age of 2.5 years is improved in infants whose mothers received high dose fish oil during pregnancy51 and observational studies have discovered that human milk DHA levels are positively correlated with visual development in breast-fed infants 52, 53. Although some studies that evaluated lactating women receiving either an omega-3 LC-PUFA supplement or placebo did not find a difference between groups54, 55, 56, several studies identified a significant positive correlation between visual acuity and milk DHA levels or infant DHA status 48-54, 56. Other studies have evaluated the effect of infant formula LC-PUFA supplementation on visual development. Some studies reported positive results, whereas others (a number of which used very low levels of DHA) found no statistically significant difference between formula groups 57-59.

B) LC-PUFA and Cognitive development
The effect of LC-PUFA on cognitive development has also been assessed. Studies have employed a variety of tests for general development, psychomotor developmental, problem solving and language development. Evidence from epidemiological studies suggests there is an association between higher levels of maternal fish consumption during pregnancy and developmental outcomes. Higher maternal fish consumption during pregnancy has resulted in short term benefits for infants such as higher novelty preference on visual recognition memory60, and longer term benefits like higher scores of verbal intelligence quotient and other behavioral outcome measures in the children up to an age of eight years61. In breastfed infants, higher DHA status at two months leads to better language production and comprehension at 14 and 18 months of age62,63.  Jensen et al.64 found that children of lactating mothers given a daily DHA supplement had significantly better scores in psychomotor development. In a double blind randomized trial, maternal supplementation during pregnancy and lactation with 1200 mg DHA and 800 mg EPA led to a 4% point advantage in children’s scores on a standardized intelligence test at the age of four years65. Two other studies during lactation did not demonstrate significant improvements in cognitive development 64, 66, however, controlling all the variables involved in evaluations of breast-feeding and cognitive development is difficult which can lead to discrepancies in results. In another double-blind, placebo-controlled, randomized trial, pregnant women consumed a DHA-containing functional food or a placebo from gestation week 24 until delivery to test the hypothesis that infants born to women who consumed a DHA-containing functional food would demonstrate better problem-solving abilities and recognition memory than would infants born to women who consumed the placebo during pregnancy. The Infant Planning Test and Fagan Test of Infant Intelligence were administered to infants at age nine months and treatment with DHA had a significant effect on the performance of problem-solving tasks but there were no significant differences between groups in any measure of Fagan Test of Infant Intelligence67. Finally, the data from a food frequency questionnaire on seafood consumption in 11,875 pregnant women at 32 weeks’ gestation was used to compare developmental, behavioural, and cognitive outcomes of children (age six months to eight years) in women consuming none, some (1–340 g per week), and >340 g of fish per week. After adjustment, maternal seafood intake during pregnancy of less than 340 g per week was associated with increased risk of their children being in the lowest quartile for verbal intelligence quotient (IQ) compared with mothers who consumed more than 340 g per week. Low maternal seafood intake was also associated with increased risk of suboptimum outcomes for prosocial behaviour, fine motor, communication, and social development scores68.

C) Is DHA necessary during pregnancy and while breastfeeding for adequate cognitive development?
Jacobsen et al. 200869 examined the relationship between cord plasma docosahexaenoic acid (DHA) concentration, gestation length, birth size, growth, infant visual acuity, cognitive, and motor development and also looked at the effects on growth and development associated with DHA intake from breast-feeding. After controlling for contaminant exposure and other potential confounders, higher cord DHA concentration was associated with longer gestation, better visual acuity and novelty preference at six months, and better mental and psychomotor performance at 11 months. By contrast, DHA from breast-feeding was not related to any indicator of cognitive or motor development in this full-term sample. Their association of higher cord DHA concentration with more optimal visual, cognitive, and motor development is consistent with the need for substantial increases in this critically important fatty acid during the third trimester spurt of synaptogenesis in brain and photoreceptor development. Several other studies have in fact found significant improvements in visual/cognitive development in children whose mothers took an omega-3 supplement while breast feeding65, 67, 68. However, the results of this study suggest that mothers should also include omega-3 supplementation in their diet while pregnant in order to guarantee improvements in motor and cognitive function.

D) Effects on infant blood pressure, immune response, atopic dermatitis cardiovascular risk, diabetes, and bone mass
Dietary supplementation of infant formula with DHA and AA has been associated with lower blood pressure at the age of six years70 and children fed a formula with DHA and AA had significantly lower mean blood pressure and diastolic blood pressure at six years of age compared to controls. Since blood pressure tends to track from childhood into adult life, early exposure to dietary LC-PUFA might have lasting effects on reduced blood pressure and cardiovascular risk. In an animal study it was determined that postnatal hypertension cardiovascular problems are programmed by perinatal diet, and that these negative cardiovascular outcomes are alleviated by maternal fish oil supplementation. Cardiac structure was examined, and rats fed a low protein diet had a thicker left ventricle and mild hypertension which was subsequently minimized with fish oil supplementation71.

There are also indications that early LC-PUFAs modulate immune system responses. A study in preterm infants demonstrated that lymphocyte populations, cytokine production and antigen maturity were similar between infants receiving human milk and an LC-PUFA supplemented formula, whereas infants receiving an un-supplemented formula differed in all these parameters72.

Studies also suggest that omega-3 fatty acid supplementation can help prevent allergic disease in children at risk. Infants born to atopic pregnant women who were randomized to receive a high dose fish oil supplement during the second half of pregnancy demonstrated an improved response to antigen skin prick test at age one year and less severe atopic dermatitis compared to infants whose mothers received a placebo73. In another study, the data from a group of women (n = 462) enrolled during pregnancy, whose offspring were followed up to six years was analyzed to assess the impact of fish consumption (assessed by food questionnaire) during pregnancy on the incidence of asthma and atopy. Thirty-four percent of infants had a medical diagnosis of eczema at age one year, 14.3% of the children were atopic (based on a skin prick test at six years), and 5.7% portrayed atopic wheeze at age six years. After adjusting for potential confounding factors, fish intake during pregnancy was protective against the risk of eczema at age one year, a positive skin prick test for house dust mite at age six years and atopic wheeze at age six74. Whether increasing maternal intake of n-3 PUFAs in pregnancy affects offspring risk of asthma was assessed in 533 women. After 16 years, children whose mother received fish oil, depicted a hazard rate of asthma that was reduced by 63% and a hazard rate of allergic asthma, that was reduced by 87%75.

Intake of fish oil can also prevent gestational diabetes by increasing insulin sensitivity76. Diabetes and impaired glucose tolerance during pregnancy create potential problems in the mother and fetus, namely an increased risk of malformations in the fetus, preeclampsia, respiratory problems, and even death of the fetus. Many of these risks can be decreased by blood glucose regulation levels during pregnancy. It is possible that offspring of mothers with diabetes are at increased risk of having disorders that may later in life result in disease thus by increasing the intake of fish oil containing omega-3 fatty acids to change prostaglandin production could be a valuable tool.

Finally, studies have also shown that the content of LC-PUFA in maternal cord blood is predictive of bone mass in healthy term infants77.

Fish oil supplements or increased fish consumption?
Numerous studies have evaluated the effects and safety of LC-PUFA supply to pregnant and lactating women78. These studies have taken into account the use of DHA alone or fish oils with various levels of DHA and EPA. Fish consumption may increase the exposure of the mother and fetus to contaminants such as mercury, dioxins and polychlorinated biphenyls (PCB) and may also increase the levels of these contaminants in breast milk. Sources of LC-PUFA during the first year of life include human milk, infant or follow-on formula enriched with LC-PUFA and complementary foods such as egg, fatty fish, and meat. Safety is of primary importance. Highly refined oils from fish for example as sources of DHA and/or AA are appropriate for use in infant formulae and weaning foods if the purity and safety of the specific oil used has been documented.

Dosage of fish oil
The Perinatal Lipid Nutrition Project (PeriLip) and The Early Nutrition Programming Project (EARNEST) in collaboration with several international scientific societies, recently developed consensus recommendations concerning dietary fat intake for pregnant and lactating women, based on a systematic review of available evidence and a formal consensus process. The consensus document recommends an average DHA intake of at least 200 mg/day during both pregnancy and lactation. However, intakes of up to 1 g/day DHA or 2-7g/day fish oil have been used in randomized trials without occurrence of adverse effects79.

DHA + GLA supplementation to prevent decreases in physiological AA
DHA and AA are found in high concentrations in structural lipids of the central nervous system and have been shown to be important for brain development and function. However, whether or not dietary supplementation with fish oil as source of omega-3 fatty acids reduces the omega-6 fatty acids gamma-linolenic acid (GLA), dihomo-GLA (DGLA) and AA concentrations in plasma and erythrocytes has led to mixed results80-88. As mentioned, AA is the second most abundant LC-PUFA in the brain, and AA derived eicosanoids are important functional mediators89. Whereas DHA has been investigated in several prospective trials, the possible relevance of AA for development and function is yet to be confirmed in clinical settings. There is limited evidence for a beneficial effect of AA on brain development and function, when it is given in combination with DHA to term infants90. Also, whether or not a reduction in AA from DHA supplementation interferes with DHA induced functional benefits is not known. Because of this, supplementation with DHA should not compromise maternal and neonatal AA status. A significant, positive relationship has been observed between DGLA status and birth weight91, GLA may be essential in the transcription of genes involved in glucose and lipid homeostasis92,93 and GLA is thought to reduce the risk of atopy94, 95. GLA thus seems to positively influence infant development while it also provides a simple way to avoid the decrease of maternal and neonatal GLA, DGLA and AA levels with DHA supplementation. A recent study did in fact demonstrate that a combined fish oil/evening primrose oil (source of GLA) intake resulted in an increase of plasma GLA, DGLA, and DHA levels without impairing the AA status96.

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This research is not intended to diagnose, treat or cure any illness or disease.