Ear!v Human Development, 12 (1985) l-8 Elsevier

EHD 00684

Review article

Maternal nutrition in pregnancy and later achievement of offspring: a personal interpretation

John Dobbing Department of Child Health, The Medical School, Oxford Road, Manchester Ml3 9PT. England

maternal nutrition: fetal nutrition; pregnancy nutrition; development of intellect

The question whether maternal nutrition in pregnancy may affect the growth of the future child’s brain, and hence its mental or neurological function, is one which brings together a number of contentious and much misunderstood topics, none of which is as readily resolved as is sometimes supposed. These include the effects, if any, of maternal nutrition on fetal growth; the possible effects on fetal brain growth of modifications of fetal bodily growth; and whether brain function, especially mental function, is likely to be altered by any such restrictive effects on brain structure at this early stage of life. These three topics will be considered in turn in an attempt to assess their bearing on the original question.

Maternal nutrition in pregnancy and fetal growth

This is a matter of considerable controversy [3], many believing that fetal growth is effectively spared by maternal nutrition, while others take an opposite view, pointing especially to intervention studies which seem to show that low birth weight, and hence reduced fetal growth, can be corrected by maternal nutritional supple- mentation, and must therefore have been due at least in part to maternal undernutri- tion. Such intervention studies are notoriously difficult to do properly in the practical circumstances of indigent society, and in the strictly scientific sense can all be flawed. There are several in the first group in which the supplementation, sometimes on a massive scale, has failed to increase birth weight [13]; and others in the second [12] in which fetal growth appears to have been measurably improved.

There is no question that dietary restriction in pregnant animals can reduce birth weight, whether in common laboratory species or in farm livestock [19]. The design of animal studies, however, can be much more easily controlled, so that there is little extraneous interference with the question being asked. In human studies, especially in conditions of poverty, the situation is quite otherwise, deliberate and measured manipulation of dietary intake as an isolated intervention over a long gestational

0378-3782/85/$03.30 0 1985 Elsevier Science Publishers B.V. (Biomedical Division)

2

period of 40 weeks in a sufficient number of women being very difficult if not impossible. The many other environmental factors which may also affect fetal growth, such as the nutritional state and other health status of impoverished women, both at the beginning of, and during pregnancy, will be found to be very heteroge- neous. Their habitual non-pregnant dietary intake is extremely difficult to assess accurately, and (he very different admixture of intercurrent, and sometimes sub- clinical disease, together with great variation in a largely unmeasurable energy output and differing genetic and possibly ethnic potential, makes a tidy experimental design and a totally convincing analysis impossible, however strenuous the attempt to control this host of potential variables. In many allegedly developed societies such dangerous habits as cigarette smoking during pregnancy and voluntary, sometimes addictive exposure to other substances which impose powerful modifications on fetal growth, coexist with all the other factors and make the investigation even more difficult. In other words the list of common environmental factors which reduce fetal growth rate is long. They often accompany malnutrition, they are usually difficult to detect, and certainly to measure reliably, and a combination of all these problems thus interferes with meaningful analysis.

In such circumstances all that can be done is to look for reasonably convincing trends amongst the many field studies, and the reviewer, rather unsatisfactori1.y but nonetheless inevitably, finds himself forming an opinion in the absence of facts which can be objectively assessed. Such in any case is often the case in human biology and clinical judgement, and this must be faced for what it is unless the enquiry is to be abandoned. The alternative is to be persuaded by the apparent purity of many epidemiological studies whose authors when carefully scrutinised, have glossed over the inevitably inadequate quality of many ol their data and the rather more avoidable lacunae in their own appreciation of the biological facts of life.

Pregnancy is associated with important alterations of metabolic mechanisms, many of which appear to be adaptations which protect the fetus from large variations in the external environment, especially including maternal dietary intake. About 5 or 6 kg of new tissue have to be constructed, both fetal and non-fetal, the latter in the placenta, uterus and breasts; and much the greatest amount is synthe- sised in the, last one third of gestation. Paradoxically there is little, if any, extra maternal dietary intake during any part of human pregnancy: indeed in the important vital last trimester most women probably eat less than they usually do [14], perhaps for reasons of comfort. The ingredients of the new tissue and the metabolic energy for its construction therefore seem to come not from increased dietary intake, but from new and transient mechanisms for storage of what is eaten in the earlier part of pregnancy for donation to the fetus in the later part when it is growing fastest, and perhaps also for lactation. The availability of ingredients for the synthesis of ‘new’ material is made possible according to this concept by retaining what would otherwise be excreted. This has been recognised for some time in the case of fat [ll] and seems also to be the case for protein nitrogen [13].

It can therefore be conjectured that in adversity these mechanisms tend to protect the fetus from maternal food shortage, and such a defence may well be totally

3

successful. Such, at any rate, is probably the case where pre-pregnancy nutritional and health status is reasonably good, where intake during pregnancy is above a certain level, where the energy output in terms of physical work is not excessive, and where any other adverse factors are moderate. In these circumstances supplementa- tion, however massive and whatever its quality, is not to be expected to increase a birth weight whose genetic potential may well be being already realised, even in relative poverty.

By contrast, in more severe impoverishment. where maternal undernutrition is prolonged and severe, where the physical labour of women is traditionally hard, where intercurrent disease and debility are rife. where short birth spacing and repeated pregnancy followed by unreasonably prolonged lactation have drained the maternal organism throughout her reproductive lifetime so far, including during adolescence, so that pregnancy begins in a depleted mother: in these circumstances it is perhaps predictable that the normal, protective, adaptive metabolic mechanisms of pregnancy may be defeated. In these cases fetal growth, especially in the last trimester, is likely to be slow, leading to potentially avoidable low birth weight. Few of the sources of adversity enumerated above are truly measurable, but on a simplified hypothesis, taking only nutrition into account, there may well be a level of intake above which supplementation would be without effect, but below which it would be measurably advantageous to fetal growth. In view of the interdependence of all the other environmental factors such a concept that there may be a ‘threshold’ is unlikely to be definable, certainly not exclusively, in terms of dietary intake: but there are already hints of the existence of such a ‘threshold’ which may, all else being equal, be in the region of 1700 to 1800 kcal per day.

This first emerged as a possibility in the analysis of the consequences of the Dutch hunger winter [17]. It was also compatible with findings from an intervention study by the same group that supplementation of indigent ladies in New York who were already eating upwards of 2200 kcal per day was without measurable effect

[161. A review of the general trend of other intervention studies in developing coun-

tries, most of them with greater, and in most cases inevitable imperfections, shows them to be equally supportive of the idea that human fetal growth can be reduced by maternal undernutrition [12]. It may be that the controversy and apparent conflict of available evidence may be resolved along the lines of a threshold as described above.

However this may be, a reduction in birth weight for gestational age at term of more than about fifteen percent due to maternal undernutrition is not often encountered in any species, including man. It is also very important to appreciate that nutritional level has never in any way been shown to be associated with shortened gestation and hence low birth weight due to prematurity. Our major question is therefore not concerned with the neurological or mental hazards of prematurity, which are well documented, but with the functional outcome of ‘smallness-for-dates’ or intrauterine growth retardation, the result of fetal growth restriction in the last trimester. In passing it is worth reflecting that ‘small-for-dates’ babies are probably not commonly the consequence of maternal undernutrition in developed countries, where most orthodox obstetric opinion originates, and where

4

they comprise about three percent of births. By contrast in developing countries the majority of babies are almost certainly small-for-dates mainly for nutritional rea- sons, and maternal undernutrition is therefore likely to be the commonest cause by far in world terms.

Nutritional growth restriction and the developing brain

As far as is known, fetal brain growth restriction of nutritional aetiology, like that occurring postnatally, is a simple and natural accompaniment of bodily growth restriction as a whole. In spite of much folklore, both ancient and modern, there is no specific food for the brain, whose growth will therefore not be impeded directly by any specific nutritional deficiency, fish and polyunsaturated fatty acids notwith- standing. Instead there is a harmony of bodily growth and organ growth and development in which the brain participates. It will grow well or otherwise in harmony with the rest of the body, in fetal as in postnatal life.

This is not to say that nutritional growth restriction affects all organs and tissues to the same extent. Some appear to be more ‘spared’ than others. In addition some are affected differently at different times of growth, a fact which is partly related to an asynchrony of their major growth spurts, such that at certain early stages when the brain growth spurt normally precedes that of other organs it will be particularly vulnerable. The ‘sparing’ phenomenon also reflects a hierarchy of degrees of susceptibility in which the liver, for example, is especially affected, and skeletal and tooth growth much less so, with the brain somewhere in between, but nearer to the more ‘spared’ end of the spectrum.

A feature of brain growth restriction which is very prominent, although not unique amongst the tissues, is that long-term failure to catch up following develop- mental retardation is closely associated with the timing of the restriction in relation to the complex sequence of regional and histological assembly of its component parts. Those regions and components of the brain which are being assembled at the time of the restriction will be specifically affected, and since brain development consists of a very complex sequence of different events, differently timed in different regions, the’ results of undernutrition will vary very much according to its timing [4,5]. Thus the general growth spurt in brain weight is compounded of a sequence of histological events which are themselves somewhat differently timed in different regions. Neurons, with a few exceptions, are differentiated from precursor neuro- blasts at an early stage, before mid-human gestation. This means that by 20 gestational weeks the adult numbers of major neurons are already present, and beyond this time any deficits in their number cannot be made good, since differenti- ated neurons are unable to divide. They proceed to develop their immense dendritic complexity and establish their myriad synaptic connections later, around the time of human birth and postnatally. Myelination accompanies these later processes, depen- dent as it is on a previous multiplication of oligodendroglial precursors which is itself later than neuroblast multiplication, beginning about mid-gestation and con- tinuing rapidly throughout the first two postnatal years [5]. A host of other

5

developmental events, both structural and metabolic, interdigitate in orderly se- quence, and mostly this all occurs within the general brain growth spurt period. In humans this period lasts throughout the second half of gestation and also occupies at least the first two years of postnatal life. Since the brain growth spurt is the period of its maximum vulnerability to external restrictive influences, it is important to understand that neuronal number is unlikely to be affected by undernutrition, having been accomplished before the growth spurt begins, and also at a stage of pregnancy which is too early in humans for fetal growth to be affected. Functionally serious restrictions of neuronal number, possibly resulting in microcephaly [6,7] can be produced by other environmental factors in the first half of the second gestational trimester, but almost certainly not by maternal undernutrition. The later develop- ment of those neurons, however, including their dendritic growth and the establish- ment of their synaptic connectivity, is a part of the vulnerable period and must expect to be affected [l].

In the rat, however, which is born relatively immature, at a stage of brain growth comparable with that of the mid-term human fetus, neuroblast multiplication occurs in the last one third of its gestation, and is consequently affected by gestational undernutrition. This is probably why the behavioural result in this species of nutritional restriction of brain growth by maternal undernutrition during pregnancy can be severe. Timing of stages of brain growth in relation to birth has therefore to be taken into account in any extrapolation between species [2,9]. Failure to do this has resulted in far too many studies using maternal undernutrition in rats as direct models of the same condition in humans.

In experimental studies, permanent deficits and distortions of both structure and function can be produced in the brain by quite mild undernutrition, according to the timing of the restriction in relation to developmental events [5]. We have no means of knowing whether the same occurs in humans, since there is a complete absence of meaningful examinations of previously undernourished human brain. Nevertheless careful and responsible reasoning from animal studies leads to a very strong likelihood that humans resemble all other mammalian species provided the above simple rules of cross-species extrapolation are observed. However unsatisfactory the use of animal models may be for this purpose, the impossibility of using human material unfortunately makes their use essential [8].

One of the gross regions of the brain which is particularly susceptible to growth restriction is the cerebellum. This relatively enhanced vulnerability is probably associated with its much more rapid growth than the rest of the brain, over a shorter period of time, a characteristic again demonstrable in all species including man. In humans cerebellar vulnerability is enhanced particularly in the weeks before and after full term birth, and it is tempting to relate this to the subsequent fine motor incoordination of many ‘small-for-dates’ babies [see 51.

The behavioural effects of nutritional growth restriction

In this, the third subdivision of our original question, whether maternal under- nutrition in human pregnancy affects the later achievement of her offspring, we are

6

on even more uncertain ground. A major reason is our virtual ignorance of the physical basis of higher mental function. We therefore have little idea of what to look for in terms of physical structural alterations within the brain. In addition we would have great difficulty in making the actual measurements, even if we did know and could obtain a homogeneous sample of human material in significant numbers of brains with near-identical nutritional and other history. Undernutrition does not produce brain damage, in the proper sense of the word, and it therefore does not result in identifiable scars. It merely distorts development and in this way alters quantitative relationships within the organ. It will therefore need the techniques of quantitative histology [l] to elucidate the effects, and these are either very laborious or not yet possible. They certainly have not yet been developed to the point of examining adequate numbers of brains as large and complex as the human.

Looking more directly at the question, there seems no doubt in practice that various aspects of mental function are indeed different or deficient in previously malnourished children, particularly if the timing, severity and duration of the malnutrition has been appropriate. In theory lasting effects on behaviour, if they are related to nutritional effects on physical brain growth at all, might be expected where a child has been growth-restricted for a substantial period of the time from about thirty weeks of gestation to the second birthday, and where the undernutrition has been reasonably severe. In impoverished communities in any country this might result from low birth weight for gestational age at or near term, followed perhaps by not being successfully breastfed in the first months, and suffering from the usual widespread episodes of gastroenteritis and other infective disease in the remaining period of infancy. Exclusive breastfeeding in communities as indigent as this will often only adequately support good growth for two or three months, children not infrequently being found to be marasmic at later times in the suckling period, even when exclusively breast-fed [18]. The conditions which are presumably necessary for deleterious effects on later achievement are therefore not uncommon in our world of today.

When functional competence is found to be impaired later in the lives of these children, as is very usual, it is therefore very tempting to attribute it in a simplistic way to an uncomplicated chain of causes, such as that undernutrition has impaired the physical growth of the brain, which has in turn resulted in diminished function.

Unfortunately for this hypothesis there is always, as in the other questions discussed above, a whole galaxy of other environmental adversity in addition to the undernutrition, any part of which could be an important forerunner of the altered mental function [8]. Several studies have tried very bravely to analyse multifactorial poverty in order to identify a separate role for nutrition [10,15] in intellectual outcome, and none have so far been wholly convincing. The reason is partly again that the many variables, and many of the most important ones, cannot easily be measured in a form that can be fed into a sophisticated analysis. Statistical method, however clever, stands or falls ultimately on both the quality of the data and the ability to quantitate it; and ways of quantitating such things as quality, duration and timing of infant undernutrition, and its interrelation with other adversity, emotional, educational and physical, are light years behind the capacity of modern statistical

7

and epidemiological techniques. Some, but only a little, of the difficulty can be eliminated by a proper choice and availability of comparison groups, but the most that can still be said from these studies is that undernutrition may be amongst those features of poverty which restrict later achievement.

It must also be emphasised that even if our chain of causation from fetal growth restriction, by way of permanent deficits and distortions of developing brain structure to deleterious effects on mental function survives scrutiny, it cannot be assumed that this would lead inevitably to life-long handicap. The achievements of even the most severely brain-damaged child can be perceptibly improved by ap- propriate stimulus and caring attention. How much more so is it likely that the previously undernourished child, who has no true brain damage, may be rescued by timely and similar treatment? It is to our collective shame that most undernourished children continue throughout life to exist in unalleviated poverty, sometimes emo- tional as well as educational and material, and are therefore deprived of available possibilities of recovery.

This very general review of whether maternal undernutrition during human pregnancy may specifically contribute to a diminution of later achievement has necessarily dwelt on the many circumstances which must lead any honest observer to take an agnostic view. No amount of false academic optimism should obscure the matter. If we genuinely seek amelioration for such large numbers of our children there can ultimately be no substitute for a concerted attack on the obscenity of world poverty.

References

1 Bedi, KS., Thomas, Y.M., Davies, C.A. and Dobbing, J. (1980): Synapse-to-neurone ratios of the frontal and cerebellar cortex of 30 day-old and adult rats undernourished during early postnatal life. J. Comp. Neurol., 193, 49-56.

2 Dobbing, J. (1973): The developing brain: a plea for more critical interspecies extrapolation. Nutr. Rep. Int., 7, 401-406.

3 Dobbing, J. (Ed.) (1981): Maternal Nutrition in Pregnancy: Eating for Two? Academic Press, London. 4 Dobbing, J. (1981): Nutritional growth restriction and the nervous system. In: The Molecular Basis of

Neuropathology, R.H.S. Thompson and A.N. Davison (Eds.), Edward Arnold, London. 5 Dobbing, J. (1981): The later development of the brain and its vulnerability. In: Scientific Founda-

tions of Paediatrics. 2nd edn. Editors: J.A. Davis and J. Dobbing. Heinemann, London, 6 Dobbing, J. (1984): The pathogenesis of microcephaly with mental retardation. In: Effects of Prenatal

Irradiation with Special Emphasis on Late Effects. C. Steffner and G. Patrick (Eds.), Commission of the European Communities, Radiation Protection, Report No. EUR 8067EN.

7 Dobbing, J. (1984): Pathology and vulnerability of the developing brain. In: Scientific Studies in Mental Retardation. J. Dobbing (Ed.), MacMillan and Royal Society of Medicine, London.

8 Dobbing, J. (1984): Infant nutrition and later achievement. Nutr. Rev., 42, l-7. 9 Dobbing, J. and Sands, J. (1979): Comparative aspects of the brain growth spurt. Early Hum. Dev., 3.

79-83. 10 Galler, J.R. (Ed.) (1983): Nutrition and Behaviour, Vol. 5, Human Nutrition: a Comprehensive

Treatise. Plenum Press, New York. 11 Hytten, F.E. and Leitch, 1. (1971): The Physiology of Human Pregnancy. 2nd Edition. Blackwell,

Oxford.

8

12 Lechtig, A. and Klein, R.E. (1981): Prenatal nutrition and birth weight: is there a causal association? In: Maternal Nutrition in Pregnancy: Eating for Two? Editor: J. Dobbing. Academic Press, London.

13 Naismith, D.J. (1981): Diet during pregnancy-a rationale for prescription. In: Maternal Nutrition in Pregnancy: Eating for Two? Editor: J. Dobbing. Academic Press, London.

14 Papoz, L., Eschwege, E., Pequignot, Cl. and Barrat, J. (1981): Dietary behaviour during pregnancy: the St. Antoine Maternity Hospital experience in Paris. In: Maternal Nutrition in Pregnancy: Eating for Two? Dobbing, J. (Ed.), Academic Press, London.

15 Richardson, S.A. (1976): The relation of severe malnutrition in infancy to the intelligence of schoolchildren having different life histories. Pediat. Res., 10, 57-61.

16 Rush, D., Stein, Z. and Susser, M. (1980): Diet in Pregnancy. Alan Liss, New York. 17 Stein, Z., Susser, M., Saenger, G. et al. (1975): Famine and Human Development: The Dutch Hunger

Winter of 1944/45. Oxford University Press, New York. 18 Waterlow, J.C. and Thomson, A.M. (1979): Observations on the adequacy of breast feeding. Lancet,

ii, 238-242. 19 Widdowson, E.M. (1981): The demands of the fetal and maternal tissues for nutrients, and the bearing

of these on the needs of the mother to ‘eat for two’. In: Maternal Nutrition in Pregnancy: Eating for Two? Editor: J. Dobbing. Academic Press, London.