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