The brain is largely made of fat or lipids. The reason for this high investment in lipids is because of the phenomenal network of intercell connections made with lipid-rich membranous structures. The signalling and receptor structures are made with DHA dense membranes across which information is transmitted. En route to the synapses the nerve wires have to be insulated. The insulation is achieved with other kinds of fats.
Hence the brain is quite unlike any other organ in the body. Its nutritional requirements are unlike the rest of the body where protein is a major concern for growth. During pregnancy, the placenta steals the essential lipid polyunsaturated fats (PUFA) needed for fetal brain growth and donates them to the fetus at a much higher proportion than in the maternal circulation: a process called bio-magnification (Crawford et al., 1976). After birth, the composition of human milk testifies to the priority of lipids for human brain development, as it has the least protein content of any large mammal but is rich in the essential fatty acids needed for the postnatal growth of the developing brain (Drury and Crawford, 1991).
In a different but similar context, both the immune and vascular systems have a specific investment in essential PUFA. Immune cells have to migrate to sites of infection or injury and engulf foreign material both involving rapid shape change. The vascular system requires highly elastic membranes or linings to respond to the constant pressure waves (pulse) generated by the heart. If the fat was not flexible, a rigid immune cell body could only move with difficulty and then be unable to make the huge shape changes to engulf foreign material such as bacteria. Similarly the vascular lining, if made with rigid saturated fats, would fail to respond to the blood pressure waves, crack and cause the blood to clot. In the case of the placenta, such blood clotting and vascular failure would and does deprive the fast-growing fetus of its optimum supply of energy and nutrients. These PUFA, arachidonic and docosahexaenoic (DHA) acids together with associated anti-oxidant system, moreover, are also made into hormone-like substances which regulate cell function and facilitate the response to injury and tissue repair (Min and Crawford, 2004).The most flexible but limiting essential PUFA is DHA. Thus, with the evidence of the poor status for DHA in Sudanese mothers, the priority target for prevention is to address the lipid nutrients deficiency of DHA.
The brain specific lipids of interest are arachidonic and docosahexaenoic acids which are selectively and specifically incorporated into developing vascular and neural structures during growth, development and maintenance. The evidence is that (i) mothers of very low birthweight preterm infants are likely to be nutritionally compromised regarding these essential lipids especially DHA, and (ii) postnatally, the very preterm infant, although fed with protein, mineral and energy requirements, cannot at this time receive appropriate nutrients similar to the missing lipids placental supply required for vascular and neural growth and development (Fig. 1).
Fig. 1. Very preterm infant delivered at 26-29 weeks. Note rapid postnatal loss of placental LNF. Postnatal evidence of Arachidonic Acid (AA) dropping to third of intra-uterine level despite feeding the precursor (LA, Linoleic Acid) the blood levels of which rise three to four-fold.
The placenta itself is a rapidly growing network of blood vessels designed to process the blood selectively for transfer of nutrients to the fetus. In this respect, fetal development depends on good vascular health and function.
In support of this concept, randomised clinical trials in adults and the Sickle Cell study referred to above provided evidence of cardio and vascular efficacy with the prevention of sudden death and vascular obstruction from use of Omega-3 fatty acids. (The Lyon and GISSI trials both reduced death by 40%+ within the first year.) Although there is some controversy on the design of the various trials due to the large variation in the background diets of participants, a design tailored to the conditions of prematurity and the specific needs of the developing blood vessels and brain is likely to also prevent ischaemia in the brain. In addition, supplementing preterm infants with the brain specific lipids provides evidence of cognitive and visual benefits (Birch et al., 2000; Carlson and Werkman, 1996; Willatts et al., 1998; Williams et al., 2001).However, these were healthy preterm infants and in none of these studies have the levels of the lipids been in the form or approached the quantities provided by the placenta.
Indeed, the lowest levels of brain-specific lipids are found in those born at the lowest weights and earliest gestations, i.e. those at greatest risk (Leaf et al., 1992 ; Leaf et al., 1992 ). Moreover, preterm infants are born with reduced levels of the brain-specific lipids and half the activity found in term infants, of the protective anti-oxidant enzymes which suppress peroxidative destruction to which the PUFA are highly susceptible (Phylactos et al., 1995).
In post-mortem studies of growth-restricted foetuses, there was a high coincidence of ischaemic lesions in both the brain and placenta (Burke, Tannenberg and Payton, 2008). Experimental deficiency of the Omega-3 fatty acids and anti-oxidants causes life threatening haemorrhage and ischemia in developing regions of the brain (Budowski, Leighfield and Crawford, 1987).Omega-3 deficiency compromises immune function: principles that would affect the preterm infant (Thies et al., 2001; Marques-Deak, Cizza and Sternberg, 2005). Susceptibility to infection goes together with inadequate nutrition, so the two concepts of nutrition and infection are not mutually exclusive.
The human preterm infant is born at the time of maximum fetal brain growth spurt and is thus at high risk of developmental damage. Formation of the cortex depends on the genesis and migration of neurons to form the densely packed cerebral cortex of the brain, which is responsible for cognition and many functions.
In Fig. 2 the stark contrast in neurogenesis in the fetal brain of a mother-fed Omega-3 DHA illustrates the migration of the cells from the core to the outside to form the cortex of the brain.
Fig. 2. Maternal Omega-3 DHA deficiency restricts migration of cortical neurons in rat fetal brain. Staining specifically reveals migrating cells. Data from Ephraim Yavin et al, 2009. Note the extensive neuronal migration in the fetal brain from the mother with a DHA-rich diet compared to poor staining in the case of the deficient mother.
The fetus of the mother-fed deficient diet is an example of the poverty of this process caused by the deficiency. There is good evidence that DHA is not only reponsible for signalling structures but also through its influence on nuclear receptors, instructing the DNA expression for neurogenesis and brain function. Professor Ephraim Yavin at the Weizmann Institute in Israel has provided this evidence on a maternal diet deficient in Omega-3 leading to delayed neuronal cell migration (Fig. 2) (Yavin, Himovichi and Eilam, 2009). Note that myelination is dependent on prior, neuronal formation (Brand, Crawford and Yavin, 2010).An example of how deficiency of DHA at a specific time, only affects the region of the brain growing at that same time.
Fig. 3. Brain Omega-3 deficiency: brain haemorrhage during growth spurt. A model of intraventricular haemorrhage, infant stroke and neurodevelopmental disorder. Budowski, Hawkey and Crawford (1980).
In Fig. 3, localised brain haemorrhage and inflammation in the post-natal developing chicken’s brain during the cerebellar growth support occurs if the newly hatched chick is fed an Omega-3 and anti-oxidant deficient diet. The cerebrum is unaffected as it has stopped growing at the time of hatching. The lesson for the human fetus comes from the fact that different regions of the brain develop at different times and have different compositions. Hence specific adverse events during pregnancy such as stress, illness or trauma, might only affect one or other region and hence a specific function. Even with cerebral palsy, the damage may vary leading to different types of disability.
Omega-3 deficiency means DHA deficiency for the brain, as DHA is the major and only Omega-3 fatty acid in the neurons and signalling systems. In this experimental model of brain DHA deficiency, 100% of the chickens will be dead within 30 days after hatching. The chickens stagger and die so it was called crazy chick disease. It was a field disease in the 1950s and 1960s associated with the use of old food in which the Omega-3 fatty acids and anti-oxidants had broken down. With mortality climbing the provision of purified Omega-3 alpha-linolenic acid, the DHA precursor in plants alone stopped all further mortality (see reference in Figure).
Note that the chicken can convert the plant-based Omega-3 alpha-linolenic acid to DHA. This conversion is however rate limited and is poor in humans, hence the value of providing DHA preformed in the diet.
The cerebrum in the chick is fully formed at hatching and so did not suffer. This model is a good example of how it is the region of the brain that is developing at the time of the insult that is affected, which may leave the rest of the brain intact. The human brain is of course much more complex.
Trials in term and preterm infants have established that the use of formula without DHA results in a loss of seven mental indices points and loss of visual acuity equivalent to 1.5 lines on the eye chart (Uauy & Dangour, 2009). A review of 26 RCTs in pregnancy and lactation reported benefits and no ill or side effects. (Brenna & Lapillione, 2009).This report was presented to the joint expert consultation of FAO and WHO (2008–2010) (Fats and fatty acids in human nutrition, 2010), which stated that 200mg per day of DHA alone or 250mg of long-chain Omega-3 fatty acids per day would be desirable in pregnancy. The dietary intakes of Sudanese (and indeed many south of the Sahara) is far below this recommendation (Nyuar, Khalil and Crawford, 2012; Nyuar et al., 2010).
The Avon Longitudinal Study (ALSPAC) on over 14,000 pregnancies followed the children born to eight years of age. There was a strong correlation between verbal IQ, prosocial and other behavioural scores with the amount of long chain Omega-3 (mainly DHA) eaten during the pregnancy (Hibbeln et al, 2007). The children of the mothers with the least Omega-3 intake during the pregnancy had the worst scores and those with the highest intakes had the best. This is the largest and longest study ever done.
It is important to note that in the 1960s and 1970s there was a major programme to reduce perinatal mortality in the UK, US and Australia, where recorded data on the prevalence of cerebral palsy rose three-fold amongst low birthweight infants in the UK (Pharoah et al., 1987), with a similar experience reported in Western Australia (Stanley and Watson, 1988) and in the US (Nelson and Ellenberg, 1978).That is: the clarion call to “save babies”, so prevalent today, resulted in saving babies that would otherwise have died. It is important to find a solution to avert repetition of the rise in cerebral palsy with the increase in babies saved.
This experience, combined with the experimental and human evidence, carries an important message for health ministries of developing countries, where there is a pressure to meet millennium goals of reduced maternal and infant mortality. The push for reducing infant mortality should also be associated with the prevention of neurodevelopmental disorder.
For references see Bibliography.