Post on 30-Dec-2021
C. Gopalan
'Late' Effects Of Foetal Undernutrition
The subject of maternal health/nutrition is likely to acquire a newurgency and importance in the light ofrecent evidences that maternal malnutrition and consequent intrauterinegrowth retardation (IUGR) may haveserious long-term implications, hitherto unsuspected. Earlier, it was thoughtnecessary to ensure optimal maternalhealth/nutrition mainly in orderto combatpossible problems related to the motherand infant in the perinatal and immediate postnatal periods, such as increased risk of maternal and neonatalmortality and substandard growth inchildhood.
There are now disturbing indications, so far largely based on epidemiological data, that the origin of majordegenerative diseases such as diabetes and coronary heart disease inadults, may in fact be traced to IUGRarising from poor maternal nutritionduring pregnancy. Wider recognitionof this at the policy-making levels mustobviously result in major shifts in public health policies and strategies.
To be sure, evidence in this regard is, thus far, epidemiological and'circumstantial'. There is, undoubtedly,a need for a great deal more criticalresearch and more extended observations in this area by independentgroups before the claims find universal acceptance.
Review of evidences: Beforewe go on to a consideration of theevidences suggestive of possible lateeffects of foetal undernutrition, it maybe useful to start with a review of the
elegant epidemiological studies of thelast two decades, notably those carried out by McKeigue and colleagues,pointing to the strikingly greater vulnerability of Indian migrants to foreign countries to coronary heart disease and diabetes, as compared toEuropeans and other ethnic groups1.These studies do not attribute suchincreased vulnerability to IUGR; theynevertheless could provide a stronglink in the chain of overall evidence,and lend added meaning to the studies discussed later, significantly linking IUGR with major degenerative diseases in adult life.
Syndrome X (insulin resistancesyndrome): Epidemiological studiesin different parts of the world duringthe last two decades, notably thosecarried out by McKeigue and his colleagues on Asian migrants, had shownthat mortality from coronary heart disease in men and women of South
Asian origin was higher than in otherethnic groups; and that this cannot beattributed to higher smoking rates orhigher intakes of saturated fats 2,3,4.
Non-insulin-dependent diabetes hasalso been found to be much morecommon in South Asians overseas,for example, 20 per cent in Asian menand women aged over 40 years in theUnited Kingdom as compared to 5 percent in Europeans2• Since a high proportion of South Asian patients withcoronary heart disease have been foundto be non-diabetic, increased prevalence of glucose intolerance alonecannot explain the increased coronary risk.
It has been postulated that theincreased risk of diabetes and of coronary heart disease are both part of asyndrome - syndrome X5, the centralfeature of which is insulin resistance.The other features of the syndromeare hyperinsulinaemia, hypertriglyceridaemia, low concentration of highdensity lipoprotein (HDL) and hypertension. Resistance to insulin-stimulated glucose uptake, leading to glucose intolerance and hypertension,and failure of insulin to suppress release of non-esterified fatty acids fromadipose tissue, leading to hypertriglyceridaemia and low HDL, are believedto be the central biochemical defects.Insulin resistance in this syndrome isalso prominently associated with apattern of obesity in which a highproportion of body fat is depositedintra-abdominally - central (abdominal) obesity. Elevated waist to hipratio reflecting abdominal obesity isfound strongly correlated with glucoseintolerances,
Though these observations havelargely been made on Indian migrantsin foreign countries, they now haveincreased relevance to Indians in
CONTENTS
• 'Late' Effects Of FoetalUndernutrition- C. Gopalan
• Dairy Development In India- A.P. Mahadevan 4
• Foundation News/Nutrition News 8
India. The observations of Ramachandran et aF from South India, andof Chadha et a/8 from North India, goto show that diabetes and coronaryheart disease are now emerging asmajor public health problems in India'surban population. Clearly the recentescalation in the incidence of coronary heart disease and diabetes amongIndia's urban middle class is one ofthe effects of the ongoing developmental transition.
. The reported remarkable differences in the prevalence of coronaryheart disease as between urban Delhiand its rural environs8, would suggestthat the proneness of Indians to syndrome X probably finds expression inconditions of relative affluence - associated with migration to urban areas or to foreign lands. Since urbanmigration is bound to gather furthermomentum in the years ahead (atleast one-third of India's population isexpected to live in urban areas by theturn of the century), and since there isbound to be (hopefully) a progressiveascent in our country, from poverty toaffluence, the problem is bound toacquire greater dimensions in the future. It, therefore, becomes extremelyimportant to identify the factor(s) responsible for the proneness of a largeproportion of Indians to syndrome Xand not to dismiss it as probably agenetic trait.
It is in this context that the results of studies linking IUGR with increased risk of coronary heart disease and diabetes with syndrome Xneed to be examined. These studieswould suggest that syndrome X couldvery well be the late effect of maternalnutritional deprivation during criticalphases of foetal growth. From thepoint of view of public health in India,this is an important lead. Should thisturn out to be true, then the strategiesfor the prevention of coronary heartdisease and diabetes, as far as Indiais concerned, would be different fromthose being promoted and pursued inEurope and America - not emphasison reduction of intake of saturatedfats (the intake of which in any case isnot unduly high in Indian diets) but onimproved maternal nutrition in orderto combat IUGR and low birth weightsin the offspring.
Barker et aI's studies: Therehave been numerous observations onexperimental animals over the lastseveral decades clearly indicating that
deprivation of different nutrients atdifferent critical points of time duringfoetal growth could bring about permanent anatomical and physiologicaldamage to a range of organs andtissues in the offspring 9,10,11,12. Thetiming and nature of nutritional deprivation during gestation were important in determining the type of damage. These earlier observations onexperimental animals had not excitedmuch interest among those interestedin human health and disease, largelybecause their relevance to humanswas not clear. With the recent studies, notably those by Barker and hiscolleagues, these earlier observationson experimental animals have acquireda new meaning and relevance.
Barker et ars initial studies werecarried out in the United Kingdom on1,586 men born in a maternity hospital in Sheffield during 1907-192513,and on 5,654 men born in Hertfordshireduring 1911-193014. These studiesbecame possible, apparently becauseof the meticulous care with which recordsin these hospitals were entered andpreserved. Barker is now extendinghis studies with data being gatheredfrom two Indian hospitals - one inPune and the other in Mysore.
Barker et ars major observationsare briefly listed below. No attemptwill be made here to discuss theirseveral other conclusions and thehypotheses that they offer in explanation of their interesting findings. Aswas pointed out earlier, further independent studies would be necessaryto establish the validity of these farreaching conclusions.
• Standardised mortality rates fromcoronary heart disease were threetimes higher (111) in men who hadweighed 18 Ib (8.2 kg) or less at oneyear of age than in those who hadweighed 27 Ib (12.3 kg) or more (42)at one year of age14. The associationof increased mortality from heart disease with low birth weight was lessstrong than with low body weight atone year of age in the case of men,suggesting that increased risk of coronary heart disease associated withlow birth weight may, to a certainextent, be minimised through improvedweight gain during infancy, in the caseof men. Curiously enough, in the caseof women, risk of high cardiovascularmortality was more strongly associated with low birth weight rather thanwith weight at one year of age. The
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reason for this sex difference is notknown.
• The prevalence of diabetes andimpaired glucose tolerance fell from27 per cent in subjects who had weighed5.5 Ib or less at birth to 6 per cent inthose who had weighed 7.51b or more.It is postulated that in IUGR, development of endocrine pancreas is impaired and ~ cell mass is reduced asevidenced by high concentration of32-33 split proinsulin in adult Iife15. Ifthis is followed by attrition of ~ cellmass through ageing and insulin resistance, then insulin-dependent diabetes could develop.
• The prevalence of syndrome X fellfrom 30 per cent in men who weighed5.5 Ib or less at birth to 6 per cent inmen who weighed 9.5 Ib or more16.Low birth weights were associatedwith thinness, reduced mid-arm circumference and low ponderal index.It is postulated that low birth weightand thinness at birth are associatedwith abnormalities in muscle structure and funcion, and that this is themajor cause of insulin resistance.Muscle biopsies have shown that insulin resistance is associated with alow density of capillaries in muscle, alower proportion of type 1 muscle fibres and a greater proportion of type2B muscle fibres17.
These observations read alongwith those of McKeigue et aI, will indicate that syndrome X, commonly prevalent in migrant and relatively affluenturban Indians, may not be a genetictrait but the possible results of IUGR.Barker et ars subjects, who showedassociation of syndrome X with lowbirth weight, were Englishmen - notIndians. With one-third of all births inIndia falling in the low birth weightcategory (a majority of them SGA), itis to be expected that the late effectsof IUGR will be more frequently seenin the relatively affluent Indian urbanmiddle class.
• While IUGR of the symmetric typecharacterised by thinness, reducedhead circumference, reduced mid-armcircumference and low ponderal index, attributable to maternal nutritionaldeprivation in mid-pregnancy, is associated with vulnerability to syndromeX, IUGR of the asymmetric type, attributable to nutritional deprivation inlate pregnancy and characterised bynormal head circumference, shortnessand low abdominal circumference atbirth, is associated with increased risk
of coronary heart disease in adult life- raised plasma concentrations offibrinogen and low-density lipoproteincholesterol18.
A NOTE OF CAUTION
The observations and claims brieflyset out above are undoubtedly important and challenging. But acceptanceof these claims in toto in the presentstate of our knowledge, could be premature and unwise. The evidence thusfar, while being quite persuasive, isby no means conclusive.
Precisely for the reason that theabove observations of Barker et aland the connected hypotheses havefar-reaching implications with respectto public health practice, they will needconfirmation and critical validationthrough other independent studiescarried out by different teams of workerswith epidemiological expertise, beforethey find general acceptance. Recentepidemiological observations fromSweden19•2o and Finland21 run contraryto Barker et ars conclusions.
What Barker et al have observedso far is no more than an associationbetween IUGR and vulnerability tosome degenerative diseases in thoselocations where their studies had beencarried out. The question that firstneeds to be answered is whether asimilar association is demonstrable inother locations and in other environments as well. Secondly, associationof two factors need not necessarilysignify a cause and effect relationship; more evidence will be needed toestablish such a claim.
Barker et al postulate that thesusceptibility of babies who start offwith a low birth weight (small-for-date)to such diseases as diabetes, andcoronary heart disease is the result oftheir being 'programmed' in utero 'inresponse to an adverse environment'.It is not clear as to how a 'programming process' which confers increasedvulnerability to degenerative diseasesis a 'response to an adverse environment'. A simpler (if less profound)explanation could be that the deprivation of essential nutrients to the foetusin critical phases of intrauterine growthcould result in different types of organand tissue damage, the deleteriousresults of which could manifest in laterlife. This is perhaps what Barker et alactually mean. Reduced child mortality, increased longevity and rising affluence, brought on by the ongoing
developmental transition, could havemade such late manifestations increasingly possible, especially among theurban middle class.
It is also agreed that the resultsof foetal damage may become manifest in adult life only where 'amplifying' factors are present in the environment. It will, therefore, be as important to identify and combat these 'amplifying' factors as it will be to preventIUGR in the first instance throughensuring optimal maternal nutrition.
The postulate of "being programmed in utero", could carry theconnotation of preordained inevitability - almost like the Hindu doctrine ofKarma! From available data, it wouldappear that among millions of poorsubjects born with low birth weights indeveloping countries, who grow anddevelop into adulthood and who continue to live under hard conditions ofrelative deprivation, the incidence ofdegenerative diseases, including coronary heart disease, is actually muchless than in the affluent populationsof developed countries and in theaffluent sections of populations oftheir own (developing) countries. Thiswould suggest that the 'amplifyingfactors' in the environment are farmore important determinants of thevulnerability to degenerative diseasesthan IUGR.
It is tempting to draw the inference from these observations thatthose born in poverty and subject toIUGR, but who acquire affluence inadult life and adopt lifestyles characterised by the excesses and errors ofthe 'rich', are more vulnerable thanthose who are born 'poor' and remain'poor'; or those who are born 'rich'but are careful to avoid unbridledconsumption and stressful lifestylesin their adult life. If this inference isjustified, then our goal must obviously be to ensure that our futurecitizens fall in this last category, thatis, they start their life's journey without the initial disadvantages of IUGR,and that in later adult life, they avoidthe pitfalls of unbridled affluence.Victims of IUGR may be less wellequipped than those starting with goodbirth weight, to withstand the deleterious effects of environmental 'amplifying factors' in adult life.
However, the Finnish study21 mentioned above does not seem to support the above inferences. Accordingto the Finnish study, upward socio-
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economic mobility was not associatedwith increased risk of coronary heartdisease; indeed, the risks appearedgreatest in those who started low andremained low in their socio-economic
level. But then, 'upward socio-economic mobility' and 'low socio-economic status', as understood in Finland and India, could be widely different in their order and attributes. Thestarting point of 'upward mobility' inFinland may well be above the povertyline, unlike in India. Upward mobilityin Finland could thus mean an ascentfrom affluence to superaffluence, notone from poverty and deprivation toaffluence as in India. Even amongcommunities of 'low socio-economicstatus' in Finland, it is doubtful if theincidence of low birth weight deliveriesis ever as high as in India. Theseconflicting signals underscore the needfor caution at this stage and for collection of more data before major conclusions with respect to public healthpolicy become justified.
Finally, it must be pointed outthat the importance of IUGR (and LBW)as a major public health problem doesnot rest on the relatively new claimswith respect to the late effects of lUG Rdiscussed above. The effects of IUGRon child growth and development, whichare proven and well established, areserious enough to merit deep concern. Even if IUGR had no 'late' effects, it would still be a major publichealth problem. The observations onpossible late effects discussed herehave only served to reveal yet another, possibly even more sinister andominous, dimension of the problem.
References
1. McKeigue, P.M. Coronary heart disease in Indians, Pakistanis and Bangladeshis: aetiology andpossibilities for prevention (edit). Br Heart J,
67:341-342, 1992.
2. McKeigue, P.M., Shah B., Marmot, M.G. Relationof central obesity and insulin resistance with highdiabetes prevalence and cardiovascular risk in SouthAsians. Lancet, 337:382-386, 1991.
3. McKeigue, P.M., Marmot, M.G., Adelstein, A.M.,et at. Diet and risk factors for coronary heart disease in Asians innorth-west London. Lancet, 11:108690, 1985.
4. McKeigue, P.M., Marmot, M.G., SyndercombeCourt, Y.D., et at. Diabetes, hyperinsulinaemia andcoronary risk factors in Bangladeshis in London. BrHeart J, 60:390-396, 1988.
5. Reaven, G.M. Role of insulin resistance in human disease. Diabetes, 37:1595-1607,1988.
6. McKeigue, P.M., Pierpoint, T., Ferrie, J.E., Marmot, M.G. Relationship of glucose intolerance and