Babies born during the food shortage were not so badly affected as those conceived during the shortage. (Table 2)

TABLE 2

Deaths (per 1,000 births) under 12 months from malformations, by timing of conception or birth in relation to the food shortage

Even worse affected than those conceived during the shortage were the babies conceived between one and four months following the shortage, who had therefore still been in the stages of sperm and egg development when their mothers were deprived.

From Zygote to Embryo

After the first cell division the new embryo will for the first week be floating free as its cells divide, so taking on a mulberry-like appearance as it journeys to the womb. It has to rely on stores built up while still in the follicle, so adverse conditions then could be taking their toll now. Around the eighth day, about 200 cells strong, it implants in the wall of the womb. Although the most profound genetic developments, and therefore most highly susceptible stages, are over within a day or two of conception the most rapid growth rate is to follow. By the third month from conception the fertilized ovum will have grown into a developing baby two and a half million times its conception weight.

Note: The age of the fetus will continue to be referred to from date of fertilization, not to be confused with conventional dating from the first missed menstruation, which would add about a fortnight.

Organogenesis

The period before a mother knows she is pregnant, sees a health professional and has pregnancy confirmed, is the period of the greatest rate of cell division. That means that this sensitive period occurs under conditions that applied before conception and without the protection of the placenta, which is yet to form. As in other animal systems the requirements for fetal nourishment are laid down ahead of the need. ⁴⁶

Once the fertilized ovum is implanted in the uterus and becomes the embryo, the placenta gradually takes over the nutrition of the embryo from the nutrient stores that accompanied the ovum. These declining nutrient stores are the remnants of the preovulatory follicle. So this is another stage when the mother particularly needs to be steadily nourished and free from xenobiotics.

Between the 8th day and 8 weeks the organs and skeletal frame are being formed. By the end of this period, those anomalies that are going to affect the fetus are already present. ⁴⁷ Growth is determined by hormone levels, with the corpus luteum in control for the first few weeks (see above, Grandmother, Mother and Grandchild). Around one half of all early miscarriages have been reported as having chromosomal anomalies and these are likely to have their origin during the highly susceptible period around meiosis 1 and 2. These are associated with a defective corpus luteum and very likely resulting from poor nutrition or xenobiotics. ²⁴ The growing embryo is still so small in these early stages that the cost to the mother in nutrients is negligible. Animal experiments show that protein deficiency can be compensated with hormones, but nutrient deficiency or xenobiotics can depress hormone levels and so inhibit and even distort growth. Barker states: ¹³ "Metabolic adaptations to undernutrition are linked to changes in the concentrations of fetal and placental hormones and influence fetal growth. Insulin and the insulin-like growth factors . . rapidly respond to changes in fetal nutrition. . . Concentration of these hormones influence nutrient availability as well as fetal growth, while they rapidly respond to changes in fetal nutrition. . . Undernutrition in early pregnancy retards embryonic growth and may result in symmetrically small low birthweight babies."

Fetus at Risk

Though less severely, toxins still threaten the fetus. To clear any substance absolutely is impossible. Since proof of a specific effect is hard it is important to respect pointers. More and more will be written on toxins in the home, workplace and general environment, as their cumulative effects become all too evident, though beyond the scope of this paper. But we do not have to look beyond elf-inflicted toxins to perceive threats commonly unrecognised, as illustrated by animal experiment. Cannabis and its constituents have been shown, as shown in Figure 18, "to slow down DNA synthesis in pregnant rats and to reduce the growth of the fetal nervous system differentially". ²⁴

None of the many offspring showed any outward visible signs of congenital malformation when the mothers had been exposed to cannabis smoke during pregnancy. But the brains of the newborn animals had on average 35% fewer brain cells, although average body weight was only 3% lower than controls. Retardation of human brain growth, if moderate, may often pass unnoticed or without attribution of cause. Not only can toxins affect parts differentially but, since fetal parts develop at unequal rates, timing of exposure may damage differentially and undetectably. Cannabis being used less widely than tobacco or alcohol, has no convincing epidemiology in relation to reproduction. Nonetheless the presumptive risk, indicated by other mammals, should be respected. Until the public is more fully aware, parents' habits may be courting danger unawares: ²⁴

"It has been said that disaster races to meet men and women who wait for proof of danger. Safety depends on the presumption of risk. There are many grounds for presuming serious risk to the next generation from the consumption of cannabis by either parent before conception, around the time of conception and by the mother during pregnancy."

The same could be said of smoking and drinking and, at least in poorer areas, of inadequate diet. Preconception care is concerned with reducing or eliminating such risks.

4. NUTRITIONAL BACKGROUND top

Nutrient Deficiencies and Xenobiotics

Xenobiotic effects, for instance of smoking or alcohol, can be studied singly and so are simpler to understand and to describe than nutrient deficiency effects - one reason why I have looked at them first. Xenobiotics affect the body in many ways like nutrient deficiencies. Good nutrition can offset some xenobiotics effects. Distinguishing the complex interactions of the many nutrients with the body's systems is far more tricky than discerning the effects of a single xenobiotic. This perhaps is why "the effects of nutrient deficiencies on pregnancy outcome have been accepted much more slowly than the effects of toxic chemicals, although deficiencies have been shown to be equally damaging. Research has also shown that the teratogenicity (malforming property) of many chemicals is increased by low intakes of particular minerals and vitamins" . Thalidomide's teratogenicity was shown to be potentiated by any of six vitamin deficiencies . Classic animal research papers on individual nutrient deficiencies show malformations and stillbirths correlating with ten key nutrients. Eight of them are found in Table 3.

Proteins, Structural Fats, Storage Fats and Energy

Human cells are built of complex molecules, proteins and fats. These are synthesised mainly from ingested proteins, which provide the essential amino acids, and essential fatty acids (EFA's). Synthesis requires energy, which comes from carbohydrate or storage fat reacting with oxygen conveyed from the placenta or lungs by the red blood cells. The fetus does not consume fat to provide energy. Its metabolism is geared to lipogenesis (fat synthesis), which favours the development of the brain.

Structural fats are distinct from storage fats, being long chain, complex and polyunsaturated. The saturated storage fats have no double-bonds, no spare chemical bonds. Polyunsaturates, having several double-bonds, can use spare bonds to link up with other polyunsaturates into even more complex structures. It is these which give rise to the blood vessels including the placenta, the heart and, most complex, the cells of the retina and brain. More than other tissues the brain is constituted of fat, 60%. After birth the infant will require glucose as a form of energy as well as fat: 50 - 60% of energy in the mother's milk will be provided by fat.

The energy has to be transferred to the proteins or lipids (fats) being synthesised by a phosphorus compound, adenosine triphosphate, usually in association with magnesium. These two are examples of many key nutrients, which are associated with proteins in animal and plant tissue. A slow-down of adenosine triphosphate turnover slows down cell replication, growth and development. ⁴⁹

A magnesium deficit alone can lead to an energy shortfall, which will evoke an increase in blood pressure to improve supply. Hypertension does in fact correlate with magnesium deficiency. It is the disease most often associated with fetal growth retardation, also with preterm delivery and strongly with low birthweight . Magnesium is essential for the maintenance, repair and replication of the cell nucleus and genetic code, and for protein synthesis in accordance with the coded instructions, in all living cells from bacteria to humans. The damage done by magnesium deficiency does not begin in the middle of pregnancy, but can begin with damage to either male or female germ cells before mating. Over 80% of magnesium can be lost in producing white flour from wheat. Over-refinement and processing of food is suggested as increasing Western pregnancy hypertension incidence beyond that of poorer rural populations .

In animals, magnesium deficiency around the time of mating results in male and female sterility, congenital malformations and low birthweight. Magnesium deficiency damages cell nuclei, causing chromosomal abnormalities (Figure 19).

Just before mating is the time when the protein level most affects pregnancy outcome - protein starvation can reduce growth and delay ovulation, causing low birthweight and stillbirth. In the Hackney study the protein intake was 73g for the optimum birthweight group (3500-4500g), well above the 51g officially recommended for pregnant women in the UK to keep birthweights in the best range. But protein intake is highly correlated with many important 'key nutrients' such as magnesium and zinc, as well as other minerals and vitamins. It is these that are more likely to be prejudiced than protein itself. ²³

Key Nutrients and Hormones

Wendy Doyle is a dietician and sociologist, specialising in nutrition in relation to pregnancy. She has been conducting clinical studies in the effects of maternal nutrition on the outcome of pregnancy, and their reflection on sociological differences. Her studies have included Hackney and other low income inner city areas and also Hampstead for sociological contrast. Numbers of pregnancies researched, including some women recruited before conception, have been large enough to indicate the effects of specific nutrient deficiencies, and the stage at which correction proves to be effective or too late.

These essential roles of phosphorus and magnesium are reflected by their place in the top three key nutrients correlating with birthweight, in Table 3. Likewise thiamine B1 is concerned with oxidation of sugars and riboflavin B2 with oxidation of fats. Folic acid and zinc are required in higher concentrations for the synthesis of the DNA of the nucleus of new cells. ⁴⁹ For instance zinc is an essential component of DNA of the genome and the RNA of the ovular luggage. Thus, what are called 'zinc fingers' are necessary for binding the reproductive steroid hormones, oestradiol and progesterone, and the thyroid hormones, to receptors on the DNA of the genome and stimulate the transcription of the information essential for reproduction carried out by the genome. ²³ Such vital specific functions render each key nutrient irreplaceable. In Table 3 the high correlation of protein is due partly to associated nutrients. Only correlates of below median birthweight are given because no significant correlation was found with those above. Enough, it seems, is as good as a feast.

TABLE 3

Nutrients correlated with birthweights in the diet of 255 London mothers with babies below median birthweight (3270g)

Minerals		Vitamins
magnesium	.253	thiamine B1	.200
iron	.247	niacin B3	.198
phosphorus	.243	pantothenic acid	.186
zinc	.238	riboflavin B2	.183
sodium	.237	folic acid	.173
potassium	.208	pyridoxine B6	.168
copper	.188	biotin	.149
calcium	.184
Protein	.238	Energy	.212
Fibre	.225

Source: See reference 54, Table 2. and reference 49.

Among so many essential nutrients, to discover and correct deficiencies may seem a daunting task. But it is simplified because the key nutrients are always found in reproductive tissue in association with protein which facilitates subsequent growth. The energy transfer nutrients required for synthesising the large molecules needed in reproduction are found in all animals and plants, concentrated in germinal tissue including eggs and sperm, seeds and nuts, also in other tissues with high energy demands which include the heart, brain, liver and kidneys. But they are not always in the same and cooking. Both groups of Hackney mothers - optimum birthweight, 'reference mothers', and low birthweight mothers - had adequate meat, and did not lack pure protein, fatty acids or vitamins A, C, D and E. ⁴⁹

The main dietary variations between reference and low birthweight groups are summarised in Table 4.

TABLE 4.

The foods of high nutrient density showed the major intake difference between the two groups: breakfast cereals, muesli, oats, nuts, seeds, eggs, wholemeal bread, dairy produce, fruit and vegetables . Milling white flour impoverishes it, as processing food tends to. Conversely in the 1930's married women in Holmes Chapel in Cheshire knew that their local baker could provide them with a 'fertility loaf' , popular with married women throughout Cheshire. This had two main ingredients, 65% wholewheat and 35% wheatgerm, sacked off rollers in a Liverpool mill until wartime regulations stopped production. ⁴⁹ The advantage simply of wholemeal bread over ordinary white bread can be gauged from Table 5.

TABLE 5

Ratio of vitamin/mineral content of wholemeal bread to content of ordinary white bread
Manganese	4.2	Thiamin B1	1.8
Magnesium	3.5	pyridoxine B6	1.6
Zinc	3.2	riboflavin B2	1.6
Niacin B3	2.7	folic acid B9	1.5
Iron	1.8
Source: See reference 49, Table 9.

Growth continues to be controlled through hormone levels, being dependent on adequate growth of glands, as on the corpus luteum during the follicular stage described above. The whole system is interdependent. Animal experimentation has shown for instance that deficiencies of thiamine and pyridoxine and other B vitamins can cause depression of the hypothalamic-pituitary-ovarian hormonal axis. Protein deficiency has a similar effect on hormone levels. The inadequacy of some aspects of the mother's diet before conception to ensure adequate secretion of pituitary and ovarian hormones may explain the significant correlations between maternal nutrient intakes and birth dimensions. ⁵⁴

Also important in growth are thyroid hormone and therefore iodine. Iodine deficiency can damage the thyroid gland causing hypothyroidism. Most people who suffer hypothyroidism are women who have at some time become pregnant on an inadequate iodine intake, so over-stressing their thyroid gland. It is the damage to their offspring which can be serious, irreversible and only preventable by correcting iodine deficiency before conception, not after diagnosis of pregnancy. ^57,58,59 Effects can include brain damage, psychomotor retardation and intellectual impairment and reproductive impairment leading to increased rates of abortion, still births, congenital abnormalities, low birth weights and infant and young child mortality . The thyroids of pregnant women and neonates are particularly susceptible to the effects of iodine deficiency. This is of special concern because adequate thyroid hormone is essential for normal brain development during early life. ⁵⁷ Following the WHO 1992 Brussels conference and further meetings, at which these findings featured, the WHO increased the recommended iodine intake to 200mcg/day .

An important source of iodine is fish, consumption of which is currently falling in UK.

5. NUTRIENTS BEFORE AND DURING PREGNANCY top

Value of Nutrition in Advance of Pregnancy

That pregnancy outcome is affected by availability of particular nutrients has been known for decades. The first to be specified was vitamin A in 1933. Since then studies on sperm and ovum, zygote and embryo have shown that all mammals are particularly susceptible to an inadequate diet or biochemically hostile environment at this time. Nutrition surveys have found that maternal protein intake at the beginning of pregnancy is an important correlate of subsequent baby length and weight, (probably more often due to key nutrients associated with protein, than protein itself). Once a woman is pregnant, appetite in pregnancy increases under hormonal influence, so at least she is wanting to increase her intake, although she may be frustrated by, say, poverty or morning sickness. These things imply that a woman's nutritional status before conception is important to the baby. Close birth spacing increases the risk of miscarriage, congenital malformation and perinatal death because it does not give a mother time to recover from the nutritional depletion caused by the first pregnancy or time to recover a normal hormonal profile before beginning the next pregnancy. Maternal vitamin depletion results from the placental vitamin pump. Nutritional deficits do more damage to reproduction around the time of conception than later during pregnancy. Vitamin and mineral deficiencies can cause not only direct damage to embryonic development but damage to both male and female germ cells resulting in new mutations before a conception. New mutations can cause pregnancy failure or maldevelopment of the embryo.

In contrast to supplementation before conception, dietary supplementation after diagnosis of pregnancy appears to result in very small birthweight increases, except during seasonal shortages in developing countries 14, or other special circumstances. However supplementation with magnesium during pregnancy has been shown to be beneficial, and correction of other minerals may be important. For although the placenta once formed can concentrate vitamins to 5 or even 10 times maternal blood levels, mineral deficiencies are shared between mother and fetus. 54 The average daily protein intake of women during pregnancy, recorded in 15 different surveys, is shown in Figure 20.

The Hackney study revealed that, at birthweights and dimensions below the median, birth dimensions increased with maternal food consumption. For babies over the median birthweight of 3,270g, there was no significant association of maternal nutrient intakes and birthweight. Babies in excess of the median birthweight would owe it to other circumstances such as hereditary factors including height. ⁵⁴ The 255 women who had smaller babies below the median of 3,270g had significantly lower average intakes of energy, of protein, and of 15 key nutrients. This effect is corroborated by animal experiments in pregnancy outcome. Deficiencies of 15 key nutrients have been found separately to correlate with either malformations, stillbirths or both. ⁴⁹ It has long been known from the culture of cells in the laboratory that all vitamins are needed for DNA synthesis and cell replication, and that there are optimum concentrations. By 1983 about 15 different fragile sites on chromosomes had been mapped, mostly sensitive to a reduced concentration of folic acid. ⁵⁰

Folate / Folic Acid

The nutrient singled out for supplementation in preconception care has been folic acid, though many products offer folate plus other vitamins, some also with minerals. This has resulted from folate's correlation in several trials with reduced rates of congenital abnormality, particularly neural tube defects (NTD). The effects of neural tube defect are severe if not lethal. Five different defects may occur in the closure of the neural tube between day 15 and 28 from conception. ⁶⁴ Incidence world wide is of the order of 1 per 1,000 births, but varies geographically. Diet, or at least supplementation, can overcome folate deficiency which may be due to poor nutrition, a metabolic defect or a folate antagonist.

Three folate trials supplementing with a range of vitamins and minerals, showed folate-related reductions of many congenital abnormalities; of NTD's of 72%, ⁶⁵ 91%, ⁶⁶ and 100%. ⁶⁷ The 1995 Hungarian trial, unlike the previous two, included vitamin B12 and zinc. There were six NTD's in the control (trace elements only); none in the group with 800mcg/day folic acid plus multivitamins and trace elements. Folate levels of 360mcg and , much higher, 4000mcg had been tried in the previous two. Czeizel observes ⁶⁷ that both folate and vitamin B12 are known to be involved in DNA synthesis and there are other vitamin interactions which could be important in lowering NTD risk; for example folic acid polyglutamates are not well absorbed by the intestine in zinc-deficient humans. He points out that many dietary surveys have documented low intakes of zinc in women of child-bearing age, especially poor women, and that vitamin B12 may be an added risk factor for NTD . It is unclear whether the first trial achieved a lower reduction; possibly the smaller dose or absence of minerals and some vitamins. Larger trial numbers and cross-checking of elements would be helpful.

What increases in folic acid intakes should we be looking for in the UK? "In the age range 19 to 50, 12 percent of men and 47 percent of women had intakes below the RNI of 00mcg/day. Very few men and women had intakes over 400 mcg/day now considered desirable in the USA" ⁶⁹ - the lowest figure the trials indicate as advisable, combined with other micronutrient supplements. In poorer areas the recommended 400mcg would fail to raise many women above 500mcg/day. Taking into account Czeizel's greater success with 800mcg folate (as well as adding vitaminin B12 and zinc), and his comments which follow on folate use and loss in pregnancy, 400mcg would seem a poor level at which to supplement for pregnancy.

The question then is, how should the intake levels of essential micronutrients be raised, at least for women of childbearing age? Here we touch on a much wider issue. The fortification of all grain products with folate was mandatory in the USA from 1st January 1999. The decision has been prompted by research indicating that the risk of heart disease, cancer, stroke, nervous system disorders, including Alzheimer's disease, and neural tube defects may be reduced by daily intake of folate higher than is currently normal in the American population. Would the British also benefit from such fortification? There is no serious possibility of educating shoppers to give enough preference to foods with a high folate content to reach the folate and vitamin B12 intakes now considered desirable. ⁶⁹

A 1994 study 14 showed there was a steeper social class gradient for the intake of folate than for any other nutrient. Here are questions of educability and affordability. The overall best approach could be to combine education with a degree of fortification. Table 6 shows the commonest foods and their folate content.

TABLE 6

Folate in standard food portions
Food	Portion size grams	Folate per portion micrograms
Cornflakes	40	100
Lamb's liver, fried	40	96
Bovril, Marmite level teaspoon	9	94
Spinach, boiled	90	81
Potatoes, old, medium, with skin	180	63
Orange, medium	160	50
Courgette, raw	90	47
Beefburgers, quarter pound, fried	160	24
Egg, chicken, boiled	50	20
Cabbage, boiled	60	17
Wholemeal bread, medium slice	30	15
Banana	100	14
Tomato	85	14
Cod, baked	120	14
White bread, medium slice	30	9

And what folate level should be the aim? A level to counteract disease in the recipient may not be optimal for pregnancy, if only for the several factors that Czeizel points out ⁶⁷: during pregnancy there is an increased requirement for folate due to decreased absorption, accelerated breakdown , increased urinary loss and fetal transfer. Adding that oral contraceptives lower blood folate levels , he recommends substituting these, during a month's preparation for conception, with a multivitamin including folic acid. Although the 1995 Hungarian trial's seeming 100% reduction in NTD's has for comparison only 6 NTD informative offspring in the control, its combination of 800mcg folate with other specific vitamins and minerals seems the most promising guide yet.

6. FETAL AND EARLY INFANT DEVELOPMENT top

The embryonic stage complete, the fetus now depends nutritionally not only on maternal intake and stores, but on a well developed placenta. observe that the placenta grows well ahead of fetal growth, which does not really get under way until about the twentieth week after conception. In this study using the umbilical artery as a diagnostic tool, the team conclude that placental insufficiency is a major determinant of fetal growth retardation, which may be general or of specific limbs or organs. Since fetal parts develop at different stages at and different rates, retardation will depend on timing of any nutrient deficiencies or xenobiotic presence. Because the placenta provides no more than a partial screen against xenobiotics they will continue to be a threat. Alcohol, nicotine and many other drugs pass through. It is the placenta which feeds the fetus. As part of the vascular system, the placenta demands long chain derivatives of particular fatty acids, as does the brain. ⁷⁵

The Brain, the ultimate in development, and DHA

Just as supreme care is needed in regenerating the very basis of human life, the genome, so it is in achieving the ultimate in creation, the human brain. Retracing the history of the human brain helps us to understand its requirements, especially that of its most essential nutrient, the long-chain molecule docosahexaenoic acid (DHA or '22:6, n-3'); 'docosa' from Greek for 22 (carbons), 'hexa', 6 (double-bonds), n-3 the first double-bonded carbon from the methyl end, as opposed to the acid carboxyl end. - This nomenclature is typical of these numerous complex biochemicals. - Our understanding of this particular EFA has recently been updated by a team led by Crawford :

Fossil records show that oxidative metabolism became predominant about 600 million years ago, at a time when the blue-green algae had photosynthesised complex molecules including proteins, carbohydrates and lipids which were rich in n-3 fatty acids including DHA. These were associated with fish and reptiles requiring n-3 fatty acids for their reproduction. So animals' visual, nervous systems, and brains, were able to evolve in this DHA rich environment in or by the sea, but not inland. The development in Africa of homo sapiens is recently recognised, almost unanimously, as taking place not on the dry savanna but on the shores of sea and lakes. - The inland finds of early remains are explained , : "The Miocene/Pliocene history of the Great Rift Valley over the past 10 million years provides a fluctuating coastline as sea levels changed about 200 feet above and below present sea levels." - In coastal hunter-gatherer cultures, women are still responsible for collecting shellfish, offering a plentiful supply even in pregnancy and lactation. It is notable that animals, mice and rats, can desaturate enough LC PUFA for their brains, but not larger inland animals. As the guineapig evolved into a wild pig, accelerated growth meant reduced conversion of vegetable fats to DHA. As the savanna animals increased in size, so their brain size diminished almost logarithmically. Inland, fossils record, the homo Australopithecus spp. scarcely reached half a litre in 3M years. By contrast, on lakes and seashores homo sapiens' brain achieved three times that size in a tenth the time. The team comment: "We consider this association not accidental nor coincidental, but a reflection of the dramatic influence of the brain specific nutrition on the evolutionary process."

During this time ther e were plenty of molecules around very similar to DHA which might have been used for its function. Yet in our metabolism there remains no signature of their use. Quite why DHA has been irreplaceable in our evolution, and in our maintenance and especially reproduction, is yet unanswered. But there is much evidence that all through our evolution, and through our life-cycle, DHA is key. And because our bodies cannot synthesise it fast enough for our needs, its presence in the environment is key.

The next key molecule is the n-6 arachidonic acid. AA and other n-6 fatty acids were to be found richly stored in the seeds of flowering plants which emerged 70M years ago. These two molecules, DHA and AA, have been essential to the evolution of the placenta, so vital in the evolution of the larger mammalian brain. The human fetus uses 70% of calories transferred by the placenta for brain growth. DHA and AA are indispensable to the brain, nervous and visual systems, as well as to the placenta and whole vascular system on which their development depends.

This background is particularly relevant to stages of the brain's most rapid development.

The Brain and Fatty Acids

Priority in fetal development is the brain. Nerve cells in the brain are already connecting up through primitive nerve paths. 100,000 nerve cells are being produced per minute which will amount to 100 billion nerve cells by birth. Crawford and colleagues explain the demand for fats: ⁷⁵ Growth retardation in the 'vulnerable' period in which the brain is developing can result in permanent deficits and distortions. Lipids rich in essential fatty acids (long chain and highly unsaturated) account for 50-60% of the solid matter of the brain. At birth, the infant's brain is using some 60% of dietary energy - it is well known everything is sacrificed before the brain.

Crawford stated in 1993: ⁶⁹ Substantial amounts (of EFA) are also stored from conception, to provide for the third trimester fetal growth, and the needs of lactation. It is therefore prudent to make a new recommendation for EFA intakes prior to conception, to ensure the appropriate quality of lipid stores for the developmental events that immediately follow conception and thereafter.

The well-nourished mother will have stored fat towards protecting the growth of the fetus for the critical perinatal period, while still retaining sufficient fat stores for lactation. Possible life-threatening shortages can be avoided by building up stores from early pregnancy or better still, in anticipation. ⁶⁹ Babies born of low birthweight or prematurely may well have been born to mothers who were inadequately nourished. These babies tend to be born with deficits AA and DHA 74, .

DHA and AA - Deficiency in Fetus and Infant

These deficits are serious also because perinatally the mother is anyway low in AA and DHA, owing to previous placental draft. Her DHA status in pregnancy, having substantially increased until the 18th week, declines thereafter. throughout pregnancy, indicates that the mother cannot provide an optimal DHA status in the fetus or newborn. ⁸²

Deficiency of fatty acids, and nutrients associated with them, is likely to impair neural development and future performance relating to the brain. Breast milk, though it cannot normally be matched, is subject to maternal health and diet. The breast milk of strict vegetarians, who have no dietary sources of DHA, contains only a third as much DHA as the milk of women eating diets which include meat and, better, fish, ⁸³ Cow's milk, contains no more than one eighth the human milk levels of long-chain essential fatty acids, of the type specifically used in the growth of the nervous and vascular systems. ⁸⁴

Especially vulnerable is the preterm baby. Intrinsically still a fetus, the baby has left the womb prematurely during this stage of rapid brain development and when its own fat stores are still very low. With serious consequences it is missing the placental pump to concentrate important nutrients from the mother's blood. Although breast milk after preterm delivery may have higher concentrations of long-chain polyunsaturated fatty acids (LC-PUFA's), ^81,85 human milk has been fine-tuned by evolution to the needs, not of the fetus or preterm baby, but of the full-term baby. And normal birth is associated with a substantial switch from neural cell division to myelination, and therefore to saturated fatty acids. ⁸⁶ But preterm babies at birth, on transferring from placenta to breast or formula milk, suffer immediate falls in AA and DHA levels, when at no point could their need be greater. Levels drop to a low point of a third, mean value a half, thus inhibiting brain, vascular and visual development. ⁸¹ Now, born deficient in these nutrients and without fat stores of their own, preterm babies urgently need supplementation if their development is not to suffer lasting detriment. ⁸⁶

Protecting DHA and AA Status

Especially since brain developmental disorders can be permanent, proper provision should be made to protect DHA and AA status of both preterm and term infants, ensuring optimum conditions for the development of membrane-rich systems including brain, nervous and vascular systems. ⁸⁴ Formulas designed specifically for preterm infants should contain both DHA and AA: this principle has been upheld for two decades by research findings. ^{84,86,87,88,89} The effects of nutrition during the short postnatal period may be long-lasting, as with experimental animals. Children fed on (early 1990s') formula milk rather than breast milk were found to score significantly lower at one year in psychomotor performance. ^90,91,92 At 3 years, term babies on formula milk scored lower on visual and stereo-acuity and letter matching. ⁹³ At 8 years preterm babies on formula milk had lower IQ than breast fed babies. ⁹⁴ In contrast LC-PUFA-supplemented term infants, whether breast fed or formula fed, at 4 months registered higher levels of neurodevelopmental response as well as raised blood levels of AA and DHA ⁹⁵ - preterm infants could be expected to benefit even more.

Formula feeds include the EFA precursors, linoleic and &Alphalpha-linolenic acids (LA and ALA), but infants cannot in these early months convert them to AA and DHA. Term infants fed on term infant formula over 4 months, fell below those fed human milk, on levels of visual acuity and blood DHA throughout their first year of life. In contrast those supplemented with DHA sustained the same levels of visual acuity and DHA throughout the year .

What then is needed in safeguarding AA and DHA status? Crawford and colleagues summarise: ⁸⁶ The B vitamins and trace elements, so important in protein synthesis, are also required for lipid metabolism, desaturation and chain elongation. These processes can be prejudiced by poor maternal diet especially around the time of conception. Feeding preterm or full-term infants with formula that does not contain AA or DHA, compared with breast milk, which does, leads to lower plasma AA and DHA concentrations, loss of brain cortex DHA, and lower cognitive and visual developmental scores. Formulas for preterm infants still tend to be based on full-term milk fatty acid composition; that is, they are rich in LA with small quantities of ALA. Some have AA and DHA. Some have neither, despite sufficient evidence for the FAO/WHO Expert Consultation to hold that formula for preterm and full-term infants should follow human milk in this respect. Stated in 1978, this was reaffirmed in 1995. ^46,97

Yet basically the risk of premature birth, with resultant loss of placental feeding, can be reduced before conception, through good maternal nutrition and freedom from xenobiotics and disease. Furthermore Crawford suggests that a fine balance of particular fats may contribute to timing of birth. The Danish population of the Faroe Islands have a high fish intake, higher birthweights and half the incidence of preterm births compared to Danes in Denmark. Consistent with the relationship between birth status of DHA and gestational age, DHA or fish oils may increase gestational length and hence birthweight by reducing the production of birth-inducing prostaglandin synthesis from AA. ⁸¹ There is evidence that supplements can reduce prematurity. Fish-oil supplementation in the third trimester seems to prolong pregnancy without detrimental effects on the growth of the fetus or on the course of labour. ^85,98

Protecting from oxidative damage

At birth comes the sudden switch from low oxygenation through the placenta, to high oxygenation through the lungs. If the lungs and other membranes are underdeveloped the high concentration of oxygen can cause serious oxidation of tissue, resulting in hyaline (glassy) membrane disease. The well developed infant copes with this new concentration of oxygen radicals. Without defence systems to prevent destructive oxidation of tissue, oxygen-fuelled life would never have proved possible. over 10 weeks premature, means destruction of membrane architecture, tissue damage and inflammation. Crawford and colleagues comment 86 that many of the complications seen in surviving preterm infants, including major complications such as periventricular haemorrhage, retinopathy of prematurity and bronchopulmonary dysplasia, are manifestations of the same pathological entity, 'oxygen radical disease'. Saugstad summarises this very technical study as demonstrating that "preterm infants with a gestational age between 29 and 34 weeks had only 50% activity of cupric/zinc superoxide dismutase in cord erythrocytes compared with term babies". ^80,99 Judging by the correlation of adult cardio- and cerebral disorders with low birthweight, there are also adult symptoms to include in 'the one disease'. ¹³

These dangers immediately following birth emphasise the need for anti-oxidants. Contrary to earlier belief, PUFA's with their unsaturated bonds are protective and reparative. Occurring in nature with PUFA's, and acting synergistically with them, are anti-oxidants such as vitamins A, E, C and beta-carotene, but these are short in Western diets. Other vitamins, folic acid especially, and enzymes are effective antioxidants, but low birthweight babies have depressed concentrations of vitamins, retinol and zinc, required for the superoxide defence system. ^84,86

The Preterm Baby's Overall Needs

Whatever the causes of the infant's premature birth it is important to simulate conditions in the womb as closely as possible, nutritionally and physically in relation to the mother particularly. Signs are strengthening from the fields of obstetrics, maternity care and psychotherapy, that the preterm baby's unreadiness for air through the lungs and new diet through the alimentary canal, is matched by its unreadiness for complete separation from the mother's body with its familiar and comforting sensations. Prematurity of these sudden changes can be critical. Recognition of these signs by parents and professionals are helping newborns, preterm and full-term, to enjoy the much needed touching and holding, particularly of the mother's unique voice. Until full term her totally containing womb is of course best, complete with arterial swish and pulse and alimentary noises, sounds that are sometimes played on tape to comfort infants.

The more we understand as a whole the preterm child's unnatural circumstances and their causes the more we can ameliorate and even prevent them. Newborn babies, particularly preterm, need much time skin-to-skin, heart-beat to heart-beat, resting close to the breast for comfort and feeding, all things that will affect their metabolism along with their entire wellbeing.

How do preterm children continue to develop? The Lancet recently reported a study on 72 'very preterm' (as distinct from 'very low birthweight') children. Born before 33 weeks of gestation, these 'cases' at age 14-15 years underwent brain magnetic resonance imaging (MRI), as well as neurological, cognitive, and behavioural assessment. They were age-matched by 21 full-term controls. 40 of the 72 cases were found to have unequivocally abnormal MRI, compared with 1 of the 21 controls. T he cases had significantly more reading, adjustment, and neurological impairments than controls, but their behaviour was significantly related to MRI abnormality. The interpretation was that: ¹⁰⁰ "Individuals born very preterm show an excess of neurocognitive and behavioural problems in adolescence, and more than half have abnormal MRI brain scans. . . If the prognosis of very preterm infants is to be improved, structural brain abnormalities must be prevented or, at least, the prevalence reduced." Better to reduce the incidence of preterm births.

7.CONCLUSION top

From genesis of germ cells to newborn child, reproduction depends for successful outcome not only on sound hereditary material. Achievement of full genetic potential in health and acuity depends on both parents from months before conception being well-nourished and free from toxins and infection, the mother throughout pregnancy and lactation also. At any particular stage any one nutrient, or combination of nutrients, can be crucial to the baby's life-long completeness and health. We know that in many places in UK, let alone in the world, nutrition falls below a level reliable for a healthy child.

In closing this shortfall, we shall be protecting the development of many children, and their families who would have faced with them drastic lifelong suffering. Immeasurably more children will escape impairment of physical and mental acuity, which would have passed unnoticed.

As long ago as 1981 a British Medical Journal leader Preconception Clinics advised: ⁴⁷ "If obstetric care is to reduce further fetal wastage and the incidence of malformation, a better understanding of the first trimester of pregnancy is vital." The purpose of such preconception clinics would be to improve knowledge of and clinical management of "this vital, and as yet largely ignored, period of human development," including suggestions of genetic counselling, dietary advice and vitamin supplementation to help reduce the incidence of neural tube defects. It may have been prompted by a slightly earlier article in the same journal by Dr Geoffrey Chamberlain, FRCOG, describing his own work in The Prepregnancy Clinic as consultant obstetrician, Queen Charlotte's Hospital for Women, London.

Today's fuller recognition of the effectiveness of primary prevention, involving both parents in the months leading up to pregnancy, highlights the need to preclude both the unwanted and the unhealthy pregnancy. Priorities so far discerned are: both parents from some months before conception, need as far as possible to ensure adequate levels of folate and other vitamins and trace minerals, and to avoid toxins and infection. Even in the developed world, including the wealthiest countries, a substantial minority of women are short of protein, key nutrients associated with protein, essential fatty acids and energy. In poorer parts of the world, the needs are of course desperate.

The point has been made that there are two inequalities militating against the health of our children and future generations. One is the increasing differences between income groups. The other inequality is between the proportion of national budget spent on treating disease and that spent on preventative measures. Preventative measures will not only be more widely and more profoundly life enhancing; but economically also they promise to be immeasurably more rewarding . ¹⁰¹

Promoting Health through Schools is a 93 page monograph World Health Organisation 1997 technical report. ¹⁰² On p65 it emphasises the importance of the education of girls for their own health and "the health and wellbeing of their future children". On the same page it refers to micronutrient deficiencies as one of "five major health and nutrition problems especially suitable for cost-effective intervention through schools". Also page 17 refers to "policies needed at the school level . . to supplement nutrition, rectify micronutrient deficiencies". Health education in schools is a world movement of great importance, of which this WHO report is most convincing. As children learn in school to be responsible for their own health, they should understand that this is part of their personal, biological responsibility also to their children and their children's children.

ACKNOWLEDGEMENTS top

Michael Crawford first inspired me in this field and he and Arthur and Margaret Wynn have enthusiastically and painstakingly helped me throughout. My heartfelt thanks to them. I am grateful also for Dick Smithells' critique, Chris Rolles' paediatric view, Roy Ridgway's introductions through our charity International Integrated Health Association, and others too numerous to list but not to thank.

GLOSSARY top

AA arachidonic acid.
Arachidonic acid straight-chain eicosatetraenoic acid (20:4, n-6), the all-Z-(5,8,11,14)-isomer, with twenty carbon atoms and four double bonds. Formed via the (8,11,14,17)-isomer from linoleic acid, arachidonic is an important intermediate in the formation of long-chain n-3 fatty acids from (9,12,15)-linoleic acid, being formed from that acid by the desaturation at c-6 and chain elongation.
ALA alpha-linolenic acid
Alpha-linolenic acid (18:3, n-3), important in the formation of docosahexaenoic acid.
Beta-carotene a vitamin, anti-oxidant
Chlamydia a bacteria, mainly transmitted sexually and infecting cells. Effects include cervicitis and urethritis. It can be destroyed by tetracycline antibiotics.
Chromosome a structure composed of a very long molecule of DNA, and associated proteins (eg histones), that carries hereditary information in the form of genes. Chromosomes are especially evident in plant or animal cells undergoing mitosis or meiosis, where each chromosome becomes condensed into a compact, readily visible thread. In non-dividing cells chromosomes typically assume a more dispersed form called chromatin. The number of chromosomes is characteristic for the species concerned - chromosomal adj.
Corpus luteum a yellow, progesterone-secreting, glandular body formed in the mammalian ovary from a [Graafian] follicle after extrusion of an ovum.
DHA docosahexaenoic acid
DNA deoxyribonucleic acid, one of the two main types of nucleic acid consisting of a long, unbranched macromolecule formed from one, or more commonly two, strands of linked deoxyribonucleotides.
Docosahexaenoic acid any straight-chain fatty acid having 22 carbon atoms and six double bonds. Only the (all-Z)-4,7,10,13,16,19-isomer of the n-3 family, occurs naturally, being present in substantial amounts (10-15% of the total fatty acids) in fish oils, and in variable amounts (a few percent of total) in animal glycerophospholipids. It can be formed metabolically from &alpha - linolenic acid. (DHA or '22:6, n-3'); 'docosa' from Greek for 22 (carbons), 'hexa', 6 (double-bonds), 'n-3' the first double-bonded carbon from the methyl end. This is typical nomenclature for these numerous complex biochemicals.
Down's syndrome, or formerly mongolism, a kind of mental abnormality frequently associated with trisomy of chromosome 21. The condition is characterised by a small stature, a rounded head with obliquely slanted ('Mongol-like') eyes and high cheekbones, a fissured tongue with large papilliae and a characteristic palmprint. / physically/ and the degree of mental defect varies considerably.
EFA's essential fatty acids.
Embryo the structure that develops from a zygote, up to the time of birth. The structure present in the early part of gestation that develops into a fetus -embryonic adj.
Essential fatty acids any polyunsaturated fatty acid that cannot be synthesised by a cell or an organism in an amount corresponding to the need or from any dietary precursor. For mammals, linoleic acid and (9,12,15,)-linoleic acid (formerly collectively known as vitamin F) are nutritionally essential.
FAO Food and Agriculture Organisation (of the United Nations).
Fetus the embryo of a mammal in the later stages of development, from the time when the main characteristics of the mature animal can be recognised. In humans the products of conception are termed the fetus from the end of the eighth week of pregnancy until birth - fetal adj.
Folate pteroylglutamate; the anion of folic acid.
Folic acid - widely distributed members of the vitamin B complex, particularly plentiful in green leafy vegetables, liver and yeast, essential for the synthesis of purines and pyrimidines. A deficiency results in megaloblastic anaemia as in birth defects tiny children born to deficient mothers.
Follicle any small cavity or recess, possibly having a secretory or excretory function.
Genome the whole of the genetic information of an organism. It is contained as DNA in eukaryotes and prokaryotes, and as either DNA or RNA in viruses. A given organism has only one genome regardless of whether the organism is haploid, diploid or polyploid.
Germ cell any cell of the germ line, including gametes.
Gonadotropin any mammalian glyco-protein hormone that stimulates gonadal function, including follicle-stimulating hormone ( FSH) and luteinising hormone (LH).
Hypothalamus the region of the vertebrate brain lying below the thalamus and around the floor of the third ventricle, just posterior to the attachment of the cerebral hemispheres. It lies just above the pituitary gland, to which it supplies various regulatory factors -hypothalamic adj.
Hypothyroidism deficient secretion by the thyroid gland, for whatever reason. In infants it leads to cretinism; in adults the consequences include low metabolic rate, lethargy and menstrual disorders.
LA linoleic acid
LC long-chain.
Linoleic acid (18:2,n-6), the (9,12,15)-isomer, important for the formation of long-chain n-3 fatty acids.
Lipid any member of a large and diverse group of oils, fats, and fatlike substances that occur in living organisms and that characteristically are soluble in lipid solvents but only sparingly solvent in aqueous solvents. Lipids constitute one of the four major classes of compounds found in living tissues the others being carbohydrates, proteins, and nucleic acids.
Meiosis or reduction divisio a process by which the nucleus of a diploid cell divides twice with the formation of four daughter haploid cells, each containing half the number of chromosomes of the parent nucleus. Meiosis occurs during the formation of gametes from diploid cells and at the beginning of haplophase 1 those organisms that exhibit alternation of generations. Meiosos involves two rounds of cell division. The first division produces two daughter cells each with one copy of each chromosome(each still made up of two sister chromatids). A second division quickly follows, and compromising an interphase (without chromosomal replication), finally separating the two chromatids in each chromosome. Compare mitosos. - meiotic adj.
Mcg. microgram, one thousandth of a milligram (mg.).
Mg. milligram
Mitosis or karyokinesis the division of a eukaryotic cell nucleus to produce two daughter nuclei that contain identical numbers or chromosomes and that are identical genetically to the parent nucleus except where crossing over or mutation has occurred. Mitosis is normally accompanied by cytokinesis leading to division of the cell. Compare meiosos. - mitotic - adj.
Mutagen any physical or chemical agent that is capable of increasing the frequency of mutation above the spontaneous background level - mutagenetic adj.
Mutation 1 the process by which genetic material undergoes a detectable and heritable structural change, or the result of such a change. Three categories are recognised: genome mutations, in which addition or subtraction of one or more whole chromosomes occurs: chromosome mutations, in which the structure of one or more chromosomes is affected; and gene mutations, the structure of a gene is altered at the molecular level. 2. Any modified gene arising from a mutation def. 1).
Myelination formation of nerve fibre sheath.
Neonatal of, relating to, or affecting a newborn animal. For human infants the neonatal period is considered to be the first month after birth.
Neonate any newborn animal.
Neural tube the embryonic nervous system.
NTD neural tube defect.
Omega-3, omega-6 n-3, n-6 fatty acids
Oocyte a cell of an animal ovary that undergoes meiosis to form an ovum. A primary oocyte is formed by differentiation of an oogonium and that undergoes the first division of meiosis to form a polar body and a secondary oocyte. Following fertilization of the egg, the secondary oocyte undergoes the second meiotic division to form the mature ovum and a second polar body.
Organogenesis the formation and development of the organs in an organism - organogenetic adj.
Piuitary hormone - secreted by the pituitary gland, which is attached to the brain, in vertebrates the most important endocrine gland.
Polyunsaturated fatty acid any fatty acid that is polyunsaturated; ie the multiple bonds are most frequently all ethylenic and usually methylene-interrupted, the configuration of their substituents generally being Z (ie cis); eg the n-6 linoleic family, foremost of which is linoleic acid.
PUFA Polyunsaturated fatty acid.
RDA recommended daily allowance, The daily intake of a particular nutrient considered adequate to maintain health.RNI Reference nutrient intake, the amount of a nutrient which is sufficient for almost every individual, up to 97% of the population.
Saturated of long-chain molecules - having no double-bonds, all carbon bonds attached to radicals.
Spermatogenesis the formation of spermatozoa in the male reproductive system. The sperms are formed from male germ cells, spermatogonia, in the testis.
Teratogen a substance that produces malformations in embryos - teratogenic adj.
Unsaturated having at least one double-bond.
WHO World Health Organisation.
Xenobiotic 1 any substance which does not occur naturally but interacts with the metabolism of any organism. 2 of, or relating to, substances that are foreign to living systems.
Zygote any fertilized ovum before it has undergone cleavage - zygotic adj.

(Mainly extracts, reproduced by kind permission of
Oxford University Press Publishing Divisions
Great Clarendon Street, Oxford OX2 6DP.
Telephone: +44 (0) 1865 556767. Fax: +44 (0) 1865 556646.
World Wide Web: http://www.oup.co.uk
from the Oxford Dictionary of Biochemistry and Molecular Biology)

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102. WHO, (1997), Promoting Health through Schools. Technical report series 870, Geneva.

Editorial top

This time we are taking the unusual step of devoting a whole issue of the journal not only to a single topic, albeit a wide and crucially important one, but also to the efforts of a single author. The Reverend Simon House describes himself as a minister of religion and a primal integration therapist who is scientifically minded (indeed, he read Natural Science and Theology at Cambridge), and as being especially interested in the lasting effects of the interplay between person and environment throughout the human life-cycle. He has written such a substantial, well honed and generally excellent review, that we are publishing this to stand alone as what should become a very important reference work. To give a little of the background to how this all came about, I can do no better than to quote directly the author's own account:

"I have always wondered about our very beginnings and 'how things work', mechanically and in evolution. My MA is in Natural Sciences and Theology, indicates my interest in relating the spiritual and material, the psychological and bio4logical. My inspiring director of studies at Cambridge was Dr John Kendrew whose face I suddenly saw on television, several years later, as one of the DNA Nobel Prize team with Crick and Watson. I enjoyed eight years in Fisons Limited, marketing and developing new products. My focus was on health products, including Sanatogen, with some attention to agrochemicals. My boss would say, 'Simon, your job is to sit in front of a blank piece of paper and see what comes'! A lot did come, including a vision which was matched a few years later by Silent Spring, Rachel Carson's book alerting us to the destructiveness of intensive farming. Self-exploration also surprised me with recall of my earliest experiences.

In 1958 I found no one who could take in what I was trying to say, but in recent decades new methods of psychotherapy have enabled many to recall these early stages of one's life. With such insights sensitive obstetricians, Frederick Leboyer and Michel Odent particularly, began renaturalising birth to protect the invaluable intuitive processes of mother and baby throughout delivery and sustain the bond between them following birth. Through practice of Frank Lake's 'primal integration therapy', and his b44ooks, I realised increasingly, especially as a parish priest, how much our psychological wellbeing and difficulties depend on our pre- and perinatal experiences. These contribute to emotional states and behaviour including violence, not just. at an individual level but at social and global levels. Since prevention of developmental damage can be more far-reaching than healing, I retired early from parish life to have more time to 'network' and to write. I soon came upon books collating early memories recalled in psychotherapy, particularly The Unborn Child by Roy Ridgway. He and I joined forces and our priority for International Integrated Health Association has been the Health of Future Generations concept. This is promotion of the most favourable poss.ible beginnings for a child, both psychologically and physiologically.

It was through this interest that Roy had encountered Professor Michael Crawford, from whom we learnt the importance of preconception nutrition. Then at a McCarrison Society meeting in 1996, perhaps foolishly, I suggested to him that the critical effects nutrients and toxins, at stages from preconception to postnatal, should be covered in a single document. To my amazement this was met with, 'Why don't you do it? Yes, you do it!' Professor David Morley add.4ed that an inexpensive illustrative version for the 'picturate' - not just the literate - was needed for health workers globally. He kindly sent me his superb example My Name is Today (TALC - Teaching at Low Cost) on child health, society and poverty, which l should love to emulate. Flattered, challenged and only because I could see no one else for this vital task, did I doggedly set to."

Edward Kirby

Published by:
Nutrition and Health, 14, 3, 2000.