Introduction:
The n-3 and n-6 families of fatty acids are essential because they cannot be synthesized in the body, but must be obtained in the diet. Fatty acids are contained in the membranes of every cell in your body, but the essential fatty acids are particularly concentrated in the membranes of brain cells, heart cells, retinal cells and immune-system cells.
Research over the decades has shown that the best fatty acids for the human body are the polyunsaturated fatty acids also called the n-3 fatty acids. These n-3 fatty acids break down to form EPA (Eicosapentanoic acid) and DHA (Docosahexanoic acid). These two fatty acids i.e. EPA and DHA are called as essential fatty acids or EFA's.
Although DHA can be obtained from alpha-linolenic acid, (ALA) the capacity for doing so declines with age. Alpha-linolenic acid is broken down to form Eicosapentanoic acid, Docosahexanoic acid and ultimately results in the formation of eicosanoids. Moreover the primary source of DHA i.e. alpha-linolenic acid cannot be synthesized in the body and has to be obtained from diet. In fact the body's ability to break down the n-3 fatty acids to form EPA (Eicosapentanoic acid) and DHA (Docosahexanoic acid) declines and comes to a stop the moment the baby is born. So the older you are (beyond infancy), the less DHA you have and more the need for supplementation.
DHA in the brain and retina:
Most of the dry weight of the brain is lipid (fat) because brain activity depends greatly upon the functions provided by lipid membranes. Compared to other body tissues, brain content of DHA and arachidonic acid is very high. DHA is particularly concentrated in membranes that are functionally active, namely in synapses and in the retina.
Fatty acid in phosphatidylethanolamine of human gray matter cell membrane is roughly 25% DHA, 25% stearic acid, 14% arachidonic and 12% oleic acid. In the outer segments of retina photoreceptors of the eye more than 50% of the fatty acid content is DHA. It is DHA's special properties of permeability and perhaps fluidity that probably accounts for this high concentration.1
DHA accrues rapidly in the prenatal human brain during the third trimester and the early postnatal period when the rate of brain growth is maximal and most vulnerable to nutritional deficiencies. Postnatal deficiencies of DHA have specifically been found to relate negatively to visual acuity, neurodevelopment, and behavior. In general, breast milk contains sufficient amounts of long chain PUFAs, including DHA, to meet these needs, assuming the maternal diet is adequate. A study examining breast milk and DHA content in Pakistani mothers versus Dutch mothers found significantly lower amounts of DHA which were directly correlated to the decreased amount of fish eaten in North Pakistan. 2
DHA in gestation:
DHA has been seen to have an important role in the maintenance of proper gestation and in the reduction of preterm births. Evidence from human and animal studies indicates that essential fatty acids of the n-3 and n-6 series, and their eicosanoid metabolites, play important roles in gestational duration and parturition, n-3 fatty acids intake during pregnancy may be inadequate. It is also documented that supplementation with long chian n-3 fatty acids such docosahexaenoic acid may be useful in prolonging the duration of gestation in some high risk pregnancies. 3
DHA in preterm labour and birth:
Preterm births are the most common cause of low infant birth weight and infant morbidity and mortality. In the absence of infections, preterm birth is characterized by lower reproductive tissue PG production and decreased inducible cyclo-oxygenase expression. Women who deliver prematurely have increased pools of n-6 fatty acid and decreased n-3 fatty acids, despite the lower PG production. Several human pregnancy supplementation trails with n-3 fatty acids have shown a significant reduction in the incidence of premature delivery and increased birth weight associated with increased gestational duration. Supplementation with long chain n-3 fatty acids such as docosahexaenoic acid may be useful in prolonging the duration of gestation in some high-risk pregnancies. 4
In preterm infants, positive relations were observed between the amount of DHA in umbilical artery phospholipids and birth weight, head circumference, and birth length.
In addition, the essential PUFA status at birth appeared to be the strongest determinant of the essential PUFA status as the expected date of delivery. 5 therefore, a higher DHA status may benefit preterm neonates, not only in terms of their intrauterine development but also in terms of their postnatal development.
DHA in pregnancy and lactation:
Because of the decline in DHA synthesis, it is not surprising that DHA content of brain cell membranes declines. Some of the reasons that can contribute to low DHA levels cab be poor diet, multiparous pregnancy, multiple births and subsequent pregnancies close together as normalization of DHA levels after birth is low. The greatest dependence on DHA occurs in the fetus during the last trimester of pregnancy and (to a lesser extent) in the infant during the first 3 months after birth. It is during this period that brain synapses are forming most rapidly, and an infant's demand for DHA exceeds the capacity of the enzymes to synthesize it.6 In fact, 70% of the brain cells are formed before birth. The additional requirements are fulfilled by mechanism believed to concentrate DHA absorption form the mother's placenta. 7
The DHA content of the brain increases 3-5 times during the last trimester and again during the first 12 weeks after birth. DHA requirements are increased during pregnancy, as the unborn child totally dependent on the mother's DHA intake. The mother's levels provide nourishment to the unborn child via the placenta and through the breast milk after birth.
After birth, the additional needed DHA comes from the nursing mother. Rapid brain growth in the infant requires large amount of omega-3 and omega-6 essential fatty acids. Infant formulas frequently have not contained arachidonic acid or DHA. One study showed that by (or just before) age 8, children who had been breast-fed as infants has an 8.3 point IQ advantage over children who had received formula.8 The study corrected for the education and social class of the mother.
Further support for the idea that DHA is critical for brain development came from an experiment, which studied the effects of adding DHA to infant formula. At both 16 and 30 weeks of age the breast-fed and supplement-formula-fed infants showed significantly better visual acuity than the placebo-formula-fed infants. 9
Even in the best formulation the efficiency of DHA and arachidonic acid absorption by an infant is inferior as compared to the absorption from breast milk. Therefore, the best way to ensure adequate DHA during pregnancy would be to take a DHA supplement so that there are adequate levels of DHA for both mother and the fetus. The content of DHA and EPA in human milk has been increased experimentally by giving fish oil that is rich in DHA, or marine algae that contains pure DHA supplements to lactating women.10 The diet of the mother normally contains enough omega-6 fatty acids to allow her to synthesize sufficient arachidonic acid.
DHA's role in infant development:
Optimal nutrition for infants - both before and after birth - is an area of research that is being given a lot of importance. In many cases, the research has yielded unexpected results. One nutrient that has emerged as an important influence in both brain and visual development for infants is DHA.
DHA is especially critical in infant development. Research has shown that when infants receive reduced amounts of DHA, they have smaller brain development and may also have poorer visual responses to light.
How does an infant get DHA?
Before a baby is born, n-3 fatty acids are transported from the mother's blood through the placenta, and are used for membrane development in the brain and retina.11 After the baby is born, the primary source of DHA is breast milk. However pregnancy causes maternal depletion of DHA levels. In the case of multiparuos pregnancy the depletion is even more deeply felt as there is no time for the body to regain its stores of DHA as a result of which the optimal levels of DHA for the fetus is also affected. This brings in to the focus once again the need for DHA supplementation in pregnancy and lactation. A recent study in the Lancet corroborated this findings.12 After analyzing brain tissues of 22 babies who had died in their first 43 weeks, researchers noted significantly higher amounts of DHA in the brains of the breast-fed babies than in formula-fed babies. Researchers have come to notice that DHA is required for the development of the cerebral cortex (the thin folded layers of the brain's hemispheres that house billions of brain cells) and also for the numerous functions the brain is responsible for including that of signal transmission and cognitive functions.
Research has also started exploring the concept that the lower levels of this essential fatty acid are associated with neurological dysfunction, which suggests there are irreversible growth pattern that occur in the very early stages of an infant's development where DHA plays a vital role.
Indeed, the most active period of brain cell division is in the first few weeks of embryonic development, almost before a woman knows she is pregnant.13 After the second month, a fetus brain grows at a tremendously rapid pace and 70% of all energy consumed goes to brain growth. Even after a baby is born, it will still use up to 60% of its energy to feed the brain. In a related area of research, studies have shown that children who were breast-fed score higher on intelligence tests than children fed with formula. 14
DHA and its importance in retinal function:
In addition to its important role in brain development, DHA plays a vital function in developing vision sharpness, or acuity. DHA is found in high concentrations in the photoreceptors of the retina and supplies lipids to the retinal membrane. During the first six months of life, a baby's retinocortical system - which enables it to distinguish between light and dark - matures rapidly. Healthy, full-term infants have shown an average 20% improvement each month between the ages of two and seven months.15 Later on, this ability to see fine light and dark contrasts will help babies recognize facial features and expression.16 It has been noted that when levels of DHA are too low, abnormal visual functioning and peripheral neuropathy occur.17
Mechanism of action:
There are two major pharmacological actions of DHA. One is physicochemical action that comes from its structure and the other is a biochemical effect of inhibiting enzymes.
Action on brain:
The physicochemical actions are that DHA enters into phospholipids in cell membranes so as to raise the fluidity of the membrane. When DHA enters into the phospholipid membranes of synapses in brain cells, the synthesis of acetylcholine is increased there, or the activity of acetylcholine receptors are enhanced, improving the apparent activity of the receptors although there is no change in their numbers. It is though that DHA works by improving the physicochemical properties of cell membranes. In addition, the cells of vessel walls get softer, controlling the elevation of blood pressure; the substance enters into the membranes of erythrocytes, enhancing deformability of red blood cells and preventing formation of blood clots; the blood circulation is also improved, which increases oxygen delivery.
Actions on the retinal and photoreceptors:
The role of DHA phospholipids in regulating G-protein signaling is present in the context of studies with rhodopsin. It is clear that the visual pigment responds to the degree of unstauration of the membrane lipids. At the cell biological level, DHA is shown to have a protective role in the cell culture model of apoptosis in relation its effects in increasing cellular phosphatidylserine (PS), also the loss of DHA leads to a loss PS, DHA may play an important role in the regulation of cell signaling and cell proliferation. Finally progress has been made recently in NMR studies to delineate differences in molecular structure and order in biomembranes due to subtle changes in the degree of phospholipid unsaturation. 21
Actions on gestation:
The eicosanoids produced form n-3 PUFA and n-6 PUFA have opposing roles to play. Although, a healthy balance of n-3 PUFA and n-6 PUFA in the ration of 4:1 provides a proper health for all. The eicosanoids are comprised of prostaglandins, leukotrines and thrombaxanes. Eicosanoids from n-3 PUFA are responsible for vasodilation anti-platelet aggregation and anti-inflammatory properties. The hypothesis proposed is that n-3PUFA prolongs gestation in human beings by interfering with uterine production of prostaglandins, possibly by inhibiting the production of dienoic prostaglandins, primarily PGF2 alpha and PGE2, which are mediators of uterine contractions and cervical ripening. Thus DHA has been seen to be beneficial in prolonging gestation by inhibiting prostaglandins, which are mediators of uterine contraction. 22
DHA with its ability to provide proper gestation period and increase the visual acuity and the intellectual development of both terms as well as preterm babies is suitable to our environment where the rate of preterm babies is almost 10% of all babies born in India.
In the treatment of intrauterine growth retardation (IUGR):
A treatment of intravenous infusion of glucose, amino acids and emulsion enriched in essential fatty acids, linoleic and linolenic acids were given to 30 pregnant women with intrauterine growth retardation and 28 non-essential fatty acids treated cases as controls. There was a marked gain in fetal biparietal diameter and in the estimated weight of the treated group over the control group. The mean birth weight was significantly different in the two groups. Fetal biparietal diameter increased much more in patients treated with essential fatty acids at 28-34 gestational weeks than those at 34-37 weeks, which indicates that early initiate complement of n-3 and n-6 fatty acids to intrauterine growth retardation mothers may correct pregnancy-induced essential fatty acids deficiency and maternal-fetal malnutrition, which demonstrates a fetal catch-up of growth in the brain and the whole body.23
Role of EFA in Multiple pregnancy:
During singleton pregnancy, the maternal essential fatty acids status decreases progressively. After multiple pregnancy it can be expected that the neonatal and maternal essential fatty acids status is even lower. To study whether the maternal essential fatty acids supply to the fetus is a limiting factor to the neonatal essential fatty acids status, we compared the plasma phospholipids essential fatty acids status of new born multiplets (30 pairs of twins and 7 sets of triplets) with that of singletons (n=89) at birth and that of their mothers at delivery. After correction for gestational age, a slightly lower essential fatty acids status was found in maternal and umbilical plasma from multiplets compared to singletons. No relation was found between the difference in birth weights of the smallest and the largest neonate of a set of multiplets and the difference in cord plasma essential fatty acids levels. Correlation between maternal and umbilical plasma essential fatty acids levels were comparable for multiple and singleton pregnancies. Therefore, adequate dietary intake is required to guarantee an optimal neonatal essential fatty acids status, especially during multiple pregnancy.24
Dosage:
200mgs of DHA daily should be quite adequate and safe for almost all pregnant women. In comparison with some extremely high dosages of DHA used in animal experiments, a maximum of 600mgs can also be considered where there is history of imbalanced diet or a diet low in n-3 PUFA.
Conclusion:
Mothers in their third trimester of pregnancy or who is breast feeding a newborn may contribute to the development of their child's brain by taking DHA in consultation with their physician. It can also be taken even during the second trimester when the brain development of the fetus is taking place. DHA supplements can also be taken to guard against the decline brain DHA normally seen with aging.
References:
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22. Olsen SF, Hansen HS, Sorensen TI, Jensen B, Secher NJ, Sommer S, Knudsen LB. Intake of marine fat, rich in (n-3)-polyunsaturated fatty acids, may increase birthweight by prolonging gestation. Lancet 1986 Aug 16;2(8503):367-9.
23. Zhang L. The effects of essential fatty acids preparation in the treatment of intrauterine growth retardation: Am. J. Perinatal. 1997 Oct:14(9):535-7.
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N. Saleem Basha*1 and R. Rekha 2
*1 Department of Pharmaceutical Biotechnology, Mohamed Sathak A.J College of Pharmacy, Chennai, India. 2 Department of Pharmacognosy, Mohamed Sathak A.J College of Pharmacy, Chennai, India.
*1 Corresponding author.
N. Saleem Basha, Department of Pharmaceutical Biotechnology, Mohamed Sathak A. J. College of Pharmacy, Medavakkam, Chennai- 600 119, India. Tel: 919943998065.
E-mail: nsaleem_basha@rediffmail.com
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